Yutaka Kai

Activation of Akt/Protein Kinase B Contributes to Induction of Ischemic Tolerance in the CA1 Subfield of Gerbil Hippocampus

Apoptosis plays an important role in delayed neuronal cell death after cerebral ischemia. Activation of Akt/protein kinase B has been recently reported to prevent apoptosis in several cell types. In this article the authors examine whether induction of ischemic tolerance resulting from a sublethal ischemic insult requires Akt activation. Sublethal ischemia gradually and persistently stimulated phosphorylation of Akt-Ser-473 in the hippocampal CA1 region after reperfusion. After lethal ischemia, phosphorylation of Akt-Ser-473 showed no obvious decrease in preconditioned gerbils but a marked decrease in nonconditioned gerbils. Changes in Akt-Ser-473 phosphorylation were correlated with changes in Akt activities, as measured by an in vitro kinase assay. Intracerebral ventricular infusion of wortmannin before preconditioning blocked both the increase in Akt-Ser-473 phosphorylation in a dose-dependent manner and the neuroprotective action of preconditioning. These results suggest that Akt activation is induced by a sublethal ischemic insult in gerbil hippocampus and contributes to neuroprotective ischemic tolerance in CA1 pyramidal neurons.

CREB is required for acquisition of ischemic tolerance in gerbil hippocampal CA1 region.

Ischemic tolerance is well known as a neuroprotective effect of pre‐conditioning ischemia against delayed neuronal death, however, the mechanism or mechanisms underlying this effect are not fully understood. We investigated the relationship between CREB and ischemic tolerance in gerbil hippocampal CA1 neurons using CRE decoy oligonucleotide. Sublethal ischemia led to an increase in the level of CREB phosphorylation in CA1 regions while lethal ischemia did not. Experiments with NG108‐15 cells showed that adding CRE decoy oligonucleotide to culture media significantly inhibited the cell growth rate. The administration of CRE decoy oligonucleotide into gerbil cerebral ventricle decreased CREB‐DNA binding activity to 38% of the control. Pre‐treatment with CRE decoy oligonucleotide 24 h before the induction of ischemic tolerance decreased CA1 neuronal cell survival to 21% of the control. The present findings suggest that a CREB‐mediated transcription system is necessary for the induction of ischemic tolerance.

Angiographic Dilatation and Branch Extension of the Anterior Choroidal and Posterior Communicating Arteries Are Predictors of Hemorrhage in Adult Moyamoya Patients

Background and Purpose— The cause of intracranial bleeding in moyamoya disease patients is still unknown. To identify factors that contribute to bleeding, we assessed the angiographic findings of moyamoya disease patients. Methods— We examined angiograms obtained from 107 moyamoya patients; 70 manifested ischemic and 37 had hemorrhagic lesions. Patients with intracerebral aneurysms or both hemorrhagic and ischemic lesions in the same cerebral hemisphere were not included. Patients were divided into those <20 years of age (n=47) and those ≥20 years of age (n=60). The right and left hemispheres in each patient were individually classified as hemorrhagic, ischemic, or asymptomatic. Each hemisphere was assessed for dilatation and branch extension of the anterior choroidal artery (AChA) and posterior communicating artery (P-CoM) and for the degree of proliferation of basal moyamoya vessels. These data were then statistically analyzed for correlation with intracranial bleeding events. Results— The degree of proliferation of basal moyamoya vessels was not statistically correlated with hemorrhagic events. On the other hand, there was a correlation between hemorrhage and dilatation and abnormal branching of the AChA. In 27 of 37 hemorrhagic hemispheres (73.0%), this artery was dilated, and its abnormal branches served as collateral supply vessels to other regions. This phenomenon was observed in 4 of 5 hemorrhagic hemispheres from young patients; it was noted in fewer than one third of ischemic and asymptomatic hemispheres from this age group. Similarly, 71.9% of hemorrhagic hemispheres from adult patients manifested AChA dilatation and branching, and the difference between hemorrhagic hemispheres and those that were ischemic or asymptomatic was statistically significant (P <0.01). Although the incidence of dilatation and abnormal branching of the P-CoM was relatively low in hemorrhagic hemispheres from adult patients (18.8%), it was significantly higher than in the ischemic and asymptomatic hemispheres from this age group. Using dilatation and abnormal branching of the AChA and/or P-CoM as assessment criteria, we obtained high specificity (86.4%) and sensitivity (84.4%) for hemorrhagic events in adult moyamoya patients. Conclusions— In adult moyamoya patients, dilatation and abnormal branching of the AChA and/or P-CoM are strong predictors of hemorrhagic events.

Evaluation of the stability of small ruptured aneurysms with a small neck after embolization with Guglielmi detachable coils: correlation between coil packing ratio and coil compaction.

OBJECTIVE:Because it is difficult to predict the compaction of Guglielmi detachable coils (GDCs) after endovascular surgery for aneurysms, we studied the relationship between the coil packing ratio and compaction. Here, we propose a simple method for the preoperative estimation of coil compaction. Using follow-up angiograms, we studied the timing and degree of coil compaction in small terminal and side-wall aneurysms with narrow necks. METHODS:We studied 62 patients with acute ruptured intracranial aneurysms that were small (<10 mm), had a small neck (<4 mm), and were coil embolized with GDC-10s. The aneurysmal volume was calculated using the equation V = 4/3&pgr;(a/2) × (b/2) × (c/2), where a, b, and c are the aneurysmal height, length, and width in millimeters, respectively. The coil volume was calculated using the equation V = &pgr;(p/2)2 × l × 10, where p represents the GDC-10 coil diameter (0.25 mm) and l is the coil length. We recorded the maximum prospective coil length, L, as that corresponding with the volume of packed coils occupying 30% of the aneurysmal volume. Therefore, L was calculated as L (cm) = 0.3 × a × b × c, and the coil packing ratio was expressed as packed coil length/L × 100. Angiographic follow-up studies were generally performed at 3 months and 1 and 2 years after endovascular surgery. We considered coil compaction exceeding 2 mm as major compaction and recorded minor compaction when it was less than 2 mm of the empty reappeared space in the embolized aneurysm. Aneurysmal location was recorded as terminal or side wall. RESULTS:Of the 62 patients, 16 (25.8%) manifested angiographic coil compaction (10 minor and 6 major compactions); the mean coil packing ratio was 51.9 ± 13.4%. The mean coil packing ratio in the other 46 patients was 80.5 ± 20.2%, and the difference was statistically significant (P < 0.01). In all 6 patients with major compaction, the mean packing ratio was less than 50% and all underwent re-embolization after a mean of 24.9 ± 1.1 months. The 10 patients with minor compaction were conservatively treated, and the degree of compaction did not change during a mean period of 24 months. We detected 93.8% of the compactions within 12 months of coil placement. The aneurysm was of the terminal type in 5 of the 6 patients with major coil compaction. CONCLUSION:In patients who underwent embolization with GDC-10s of aneurysms that were small and had a small neck, the optimal coil packing ratio could be identified with the formula 0.3 × a × b × c. The probability of coil compaction was significantly higher when the coil packing ratio was less than 50%. To detect coil compaction after embolization, follow-up angiograms must be examined regularly for at least 12 months. To detect major coil compaction in patients with terminal type aneurysms, angiographic follow-up should not be shorter than 24 months.

Effect on Cerebral Vasospasm of Coil Embolization Followed by Microcatheter Intrathecal Urokinase Infusion Into the Cisterna Magna A Prospective Randomized Study

Background and Purpose— Vasospasm remains the leading cause of death and permanent neurological disability in patients with aneurysmal subarachnoid hemorrhage (SAH). The objective of our prospective randomized trial of coil embolization followed by intrathecal urokinase infusion into the cisterna magna (ITUKI therapy) was to test its effectiveness in preventing or alleviating the severity of ischemic neurological deficits caused by vasospasm. Methods— We enrolled 110 patients with ruptured intracranial aneurysms eligible for coil embolization and randomly assigned them to embolization with (n=57) or without (n=53) ITUKI therapy performed within 24 hours of aneurysmal SAH. The incidence of symptomatic vasospasms and the clinical outcomes, based on the Glasgow Outcome Scale, 6 months after SAH onset were assessed. Results— There were no side effects or adverse reactions attributable to ITUKI therapy. Symptomatic vasospasm occurred in 5 patients (8.8%) with and 16 (30.2%) without ITUKI therapy; the difference was significant (P =0.012). Although the mortality rate did not differ between the groups, patients with ITUKI therapy had significantly better outcomes than those without (P =0.036). Conclusions— Our results demonstrate that ITUKI therapy significantly reduced the occurrence of symptomatic vasospasm. Although it did not completely prevent vasospasms, ITUKI therapy resulted in a lower rate of permanent neurological deficits.

Neuroprotective Effect of Postischemic Administration of Sodium Orthovanadate in Rats with Transient Middle Cerebral Artery Occlusion

Orthovanadate is a competitive inhibitor of protein tyrosine phosphatases. Some of its reported biologic effects are its insulin mimetic property and its activation of phosphoinositide 3-kinase and extracellular-signal regulated kinase (ERK). The authors previously reported its neuroprotective effect on delayed neuronal death of gerbil hippocampal CA1 neurons via Akt and ERK activation after transient forebrain ischemia. In the present study, the neuroprotective effect of postischemic intraperitoneal administration of sodium orthovanadate (2 mL/kg of 50-mmol/L sodium orthovanadate in saline) was investigated in rats with transient middle cerebral artery occlusion. Ischemic neuronal injury was evaluated 1 day and 28 days after ischemia. The neuroprotective effect of orthovanadate was significant in the cortex but not the caudate putamen (ischemic core) at both 1 and 28 days after ischemia. In orthovanadate group, the activities of Akt and ERK were maintained after reperfusion; they were decreased in saline group. Blood glucose level decreased but within normal range. Regional cerebral blood flow was lower than that of saline group only at 0 hours after reperfusion. These data suggest that orthovanadate has neuroprotective effects in rats with transient middle cerebral artery occlusion and that these effects are mediated by Akt and ERK activation. Furthermore, low blood glucose levels and gradual recovery of regional cerebral blood flow may contribute to neuroprotection.

Clinical features of aneurysms of the posterior cerebral artery : A 15-year experience with 21 cases

OBJECTIVE:To investigate the characteristic clinical behavior and develop guidelines for the clinical management of posterior cerebral artery aneurysms, we reviewed 21 cases treated during a 15-year period. METHODS:Between 1988 and 2002, we treated 21 patients (10 male, 11 female; mean age, 49.8 yr) with posterior cerebral artery aneurysms at Kumamoto University Hospital and its affiliated hospitals. Data relating to the clinical, radiological, and surgical approaches were analyzed. RESULTS:There were 20 saccular aneurysms, 6 of which were giant or large aneurysms, and 1 dissecting aneurysm. Of the 21 patients, 15 presented with subarachnoid hemorrhage; in 3 patients, an unruptured saccular aneurysm was found incidentally during an evaluation for other cerebral pathological conditions. Two patients presented with progressive homonymous hemianopsia because of the mass effect of the aneurysm, and 1 patient experienced the sudden onset of homonymous hemianopsia because of thrombosis of the aneurysm and afferent artery. Open or endovascular surgery was performed in 19 patients: 14 made a good recovery, 2 had a moderate disability because of angiospasm or infarction after aneurysm trapping, 1 had a severe disability because of angiospasm and cerebral contusion, and 2 died because of severe angiospasm. Of 2 conservatively treated patients, 1 made a good recovery but the other died as a result of rebleeding. CONCLUSION:Posterior cerebral artery aneurysms have specific clinical characteristics compared with aneurysms located elsewhere. The aneurysmal site and size and the surgical technique did not significantly influence treatment outcomes.

Treatment of cavernous sinus dural arteriovenous fistulae by external manual carotid compression.

OBJECTIVEExternal manual carotid compression is a noninvasive method to treat cavernous sinus (CS) dural arteriovenous fistulae (DAVF). We studied a group of patients with CS-DAVF to identify what factors made complete resolution of their clinical symptoms and closure of the DAVF on magnetic resonance angiography (MRA) by compression therapy possible. METHODSWe treated 23 patients with CS-DAVF without cortical venous drainage or a recent decline in visual acuity by compression therapy. All were followed up by magnetic resonance angiography at 1, 3, 6, and 12 months after treatment and the characteristics of the imaging findings, their neurological symptoms, and the patterns of symptom improvement were examined. RESULTSIn Group A (n = 8), complete resolution was achieved by manual carotid compression. In the other 15 patients (Group B), complete resolution was not obtained. Group B manifested significantly higher ocular pressure and a significantly longer interval between symptom onset and compression treatment. In Group A, venous drainage was via the superior orbital vein with or without involvement of the inferior petrosal sinus. Closure of the CS-DAVF occurred within 4.1 months after the start of treatment. In three patients, symptom improvement progressed steadily and gradually. The other five patients with complete resolution experienced transient worsening of their symptoms at 2 to 4 months after the start of treatment and symptom resolution occurred within 4 to 7 months. CONCLUSIONWe identified lower ocular pressure, a shorter interval between symptom onset and compression treatment, and venous drainage solely via the superior orbital vein without involvement of the inferior petrosal sinus as the factors in our CS-DAVF patients that made complete resolution by manual carotid compression possible.

Prediction of high-grade meningioma by preoperative MRI assessment

High-grade (World Health Organization grades II and III) meningiomas grow aggressively and recur frequently, resulting in a poor prognosis. Assessment of tumor malignancy before treatment initiation is important. We attempted to determine predictive factors for high-grade meningioma on magnetic resonance (MR) imaging before surgery. We reviewed 65 meningiomas (39 cases, benign; 26 cases, high-grade) and assessed four factors: (1) tumor–brain interface (TBI) on T1-weighted imaging (T1WI), (2) capsular enhancement (CapE), i.e., the layer of the tumor–brain interface on gadolinium-enhanced T1WI (T1Gd), (3) heterogeneity on T1Gd, and (4) tumoral margin on T1Gd. All four factors were useful in distinguishing high-grade from benign meningiomas, according to univariate analysis. On multivariate regression analysis, unclear TBI and heterogeneous enhancement were independent predictive factors for high-grade meningioma. In meningiomas with an unclear TBI and heterogeneous enhancement, the probability of high-grade meningioma was 98%. Our data suggest that this combination of factors obtained from conventional sequences on MR imaging may be useful to predict high-grade meningioma.

A reevaluation of the primary diagnosis of hemangiopericytoma and the clinical importance of differential diagnosis from solitary fibrous tumor of the central nervous system.

OBJECTIVES Hemangiopericytomas (HPCs) are rare neoplasms with relatively high rates of recurrence and extracranial metastasis. Though the differential diagnoses from angiomatous meningiomas and from solitary fibrous tumors (SFTs) are both important, the latter diagnosis is somewhat more important in light of the benign prognosis of SFTs and the difficulties in distinguishing SFTs from HPCs. Newly developed immunohistochemical methods reveal differences in the specific immunohistochemical features of HPCs and SFTs. To elucidate whether SFTs have been misdiagnosed as HPCs in the past, our group used recent immunohistochemical methods to re-evaluate tissues that had been originally diagnosed as HPCs. We also compared the clinical features of these cases. PATIENTS AND METHODS Thirteen sequential cases of HPC diagnosed in Kanazawa University Hospital and Kumamoto University Hospital between 1970 and 2006 were retrospectively analyzed by immunohistochemical staining for CD34, Bcl-2, epithelial membrane antigen (EMA), vimentin, and S100 protein, and by measurement of the MIB-1 labeling index (LI). The cases were then re-evaluated and newly diagnosed based on the results of the immunohistochemical stainings. The clinical course of each case was also evaluated. RESULTS Four of the 13 cases were newly diagnosed as SFTs and eight were reconfirmed as HPCs, based on the immunohistochemical studies for CD34, Bcl-2, and reticulin staining. One case was newly diagnosed as meningioma on the basis of a strong EMA positivity. The MIB-1 LI was less than 1% in 12 of the cases. In two cases, one case of HPC and the other of meningioma, the MIB-1 LI was relatively high, 8% and 4% respectively. All eight of the HPCs recurred, and 5 of the HPC patients died of the disease. Only one case of the SFTs recurred. CONCLUSION Our study suggests that a relatively high percentage of the tumors diagnosed as HPCs in the past may have in fact been intracranial SFTs. Immunohistochemical examinations of CD34, Bcl-2, and reticulin stains are keys for the differential diagnosis. Given that SFTs have a considerably better prognosis than HPCs, it is important to carry out meticulous immunohistochemical examinations for the primary diagnosis.