Tomohito Hishikawa

Growth potential and response to multimodality treatment of partially thrombosed large or giant aneurysms in the posterior circulation

OBJECTIVEThis study examined the growth potential and response to multimodality treatment of partially thrombosed large or giant aneurysms in the posterior circulation. METHODSThe 17 aneurysms arose from nonbranching sites of the vertebral artery (VA) in 6 patients and from branching sites in 11 patients (the VA-posteroinferior cerebellar artery [PICA], 3 cases; basilar artery [BA] fenestration, 1 case; BA-superior cerebellar artery [SCA], 5 cases; and BA tip, 2 cases). RESULTSEndovascular trapping was performed in 5 VA aneurysms at nonbranching sites, 2 VA-PICA cases with or without revascularization of the PICA, and 1 BA fenestration case. Endosaccular embolization was performed in 2 BA-SCA aneurysms as the sole treatment or after superficial temporal artery-SCA bypass for a broad-necked lesion. Surgical proximal occlusion (PO) with or without revascularization of the PICA was performed in 2 VA cases. Endovascular treatment failed to prevent growth in 1 VA-PICA case and the broad-necked BA-SCA case. Simple flow alteration by PO of 3 BA aneurysms, with gadolinium enhancement on T1-weighted images, did not prevent growth. Maximum flow reduction by various combinations of bypass (superficial temporal artery-posterior cerebral artery or superficial temporal artery-SCA) and BA PO, aimed at reducing hemodynamic stress on the neck, was tailored to 5 cases, including those refractory to PO; it achieved marked shrinkage in 2 cases and stabilization of the aneurysms in 3 cases. The aneurysms harboring neither gadolinium enhancement nor hyperintensity on fluid-attenuated inversion recovery images showed significantly lower growth potential before treatment and a lesser degree of shrinkage after tailored treatment than the remaining cases (P = 0.03 and P = 0.01, respectively). Overall, marked shrinkage was achieved in 27%, moderate shrinkage in 20%, stabilization in 47%, enlargement in 7%, and favorable outcome in 71%. Maximum flow reduction strategy for BA aneurysms tended to show higher shrinking efficacy than endovascular trapping for VA and BA aneurysms (P = 0.08). CONCLUSIONFor aneurysms at nonbranching sites, endovascular trapping may be effective, although its shrinking efficacy may be moderate. For the most formidable BA aneurysms at branching sites, maximum flow reduction may cause marked shrinkage, even of aggressive lesions.

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.

Histologic characterization of mobile and nonmobile carotid plaques detected with ultrasound imaging.

OBJECTIVES Although mobile plaques in the carotid arteries detected by duplex ultrasound imaging are considered to cause unstable neurologic symptoms such as crescendo transient ischemic attack or progressive stroke, the histology of mobile plaques has not been sufficiently documented. This study examined the histopathologic features of mobile plaques of the carotid artery and compared the histopathology between mobile and nonmobile plaques. METHODS Of 228 carotid plaques assessed by preoperative carotid ultrasound imaging, 21 (9.3%) were diagnosed as mobile symptomatic plaques. Of these, 18 were intact after excision by endarterectomy and enrolled for histologic examination. From the remaining 207 nonmobile plaque specimens, 17 nonmobile but symptomatic plaque specimens were extracted for histologic comparison. An investigator blinded to the ultrasound findings assessed both plaque specimens for fibrous cap thickness, fibrous cap rupture, fibrous cap area, necrotic core size, inflammatory cells, intraplaque hemorrhage, and mural thrombus. Clinical data, including progressive ischemic symptoms after admission, were also examined. RESULTS Progressive ischemic symptoms were more frequently seen in patients with mobile plaques than in those with nonmobile plaques (33.3% vs 0%, P = .02). The ratio of the cross-sectional area of the necrotic core to that of the entire plaque was significantly larger for mobile plaques than for nonmobile plaques (mean, 0.660 vs 0.417, P < .0001). Mural thrombus was more prevalent among mobile plaques (89%) than among nonmobile plaques (59%), but the difference was not significant (P = .06). The median minimum thickness of the fibrous cap was extremely small in both groups (80 μm in mobile plaques and 100 μm in nonmobile plaques, P = .33). CONCLUSIONS The histologic characteristics of mobile carotid plaques are different from those of nonmobile symptomatic plaques, especially in the area of the necrotic core. This histologic difference may partly explain the unstable neurologic presentations of patients with mobile carotid plaques.

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.

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.

Effect of vasodilation by milrinone, a phosphodiesterase III inhibitor, on vasospastic arteries after a subarachnoid hemorrhage in vitro and in vivo: effectiveness of cisternal injection of milrinone.

OBJECTIVECerebral vasospasm remains a major cause of morbidity and mortality. Milrinone, a bipyridine phosphodiesterase III inhibitor, is a potent member of the inodilator class of cardiac agents for vasospasm and is injected intra-arterially or intracisternally. There have been no studies investigating the duration of action (context-sensitive half-life) of milrinone for vasospasm or the most effective route of administration (intra-arterial versus intracisternal). We examined the effects of intracisternal and intra-arterial injection of milrinone on chronic cerebral vasospasm in dogs. METHODSA double-hemorrhage canine model was used. In a preliminary isometric tension study of canine vasospastic basilar arteries, the vasodilatory effects of milrinone were examined 7 days after an initial injection of blood. Milrinone was injected intracisternally (0.1 mg, 0.47 mmol/L) or intra-arterially (0.3 mg/kg, 1.2 mmol/L), and angiograms were performed 30, 60, 120, 180, 240, 300, and 360 minutes later on day 7. RESULTSMilrinone produced concentration-dependent vasodilation and was effective intracisternally, resulting in significant dilation until 180 minutes after injection and a tendency for dilation until 240 minutes. The effect of intra-arterial injection was not as significant compared with an intracisternal injection, resulting in significant dilation only at 180 minutes after intra-arterial injection. CONCLUSIONIntracisternal injection of milrinone was more effective than intra-arterial injection for chronic cerebral vasospasm in dogs because intracisternal injection produced a higher concentration in vasospastic arteries (0.034–0.068 mmol/L intracisternally versus 0.016 mmol/L intra-arterially).

Virtual histology-intravascular ultrasound in assessment of carotid plaques: Ex vivo study

OBJECTIVEVirtual histology–intravascular ultrasound (VH-IVUS) has been reported to be useful in detecting the components of coronary plaques in vivo. Recently, the application of VH-IVUS to peripheral interventions has been evaluated. The aim of this study was to examine the extent to which the necrotic core of carotid plaques could be assessed accurately by VH-IVUS compared with histopathology. METHODSA total of 37 carotid plaques underwent ex vivo VH-IVUS within 24 hours after endarterectomy. Ninety-five segments of virtual histological images were matched to histological sections. The area of the necrotic core on histological sections was compared with that on virtual histological images. Intraplaque hemorrhage (IPH) was histopathologically graded by its severity using immunohistochemical staining for glycophorin A as a marker. The relationship of the severity of the IPH to the necrotic core was histopathologically evaluated. The correlation between the necrotic core or IPH with symptomatology was also evaluated. RESULTSThe area of the necrotic core on virtual histological images (median, 8.0%; interquartile range, 5.0%–13%) was significantly smaller compared with that of the histological sections (median, 50%; interquartile range, 40%–63%) (P < 0.0001). The Bland-Altman analysis showed poor agreement in the necrotic core measurement between virtual histological images and histological sections (mean difference, 39.8%; 95% confidence interval, 35.8%–43.8%). Severe IPH was significantly associated with a larger necrotic core and symptomatology (P < 0.0001 and P = 0.0039, respectively). The area of necrotic core on the virtual histological analysis did not correlate with symptomatology (P = 0.70), but that on pathological analysis tended to correlate with symptomatology (P = 0.059). CONCLUSIONIn the present virtual histological algorithm, the underestimation of the necrotic core was revealed. The lack of a hemorrhage component in the virtual histological algorithm is a leading cause of its underestimation.

Anti-high mobility group box-1 (HMGB1) antibody attenuates delayed cerebral vasospasm and brain injury after subarachnoid hemorrhage in rats

Although delayed cerebral vasospasm (DCV) following subarachnoid hemorrhage (SAH) is closely related to the progression of brain damage, little is known about the molecular mechanism underlying its development. High mobility group box-1 (HMGB1) plays an important role as an initial inflammatory mediator in SAH. In this study, an SAH rat model was employed to evaluate the effects of anti-HMGB1 monoclonal antibody (mAb) on DCV after SAH. A vasoconstriction of the basilar artery (BA) associated with a reduction of nuclear HMGB1 and its translocation in vascular smooth muscle cells were observed in SAH rats, and anti-HMGB1 mAb administration significantly suppressed these effects. Up-regulations of inflammation-related molecules and vasoconstriction-mediating receptors in the BA of SAH rats were inhibited by anti-HMGB1 mAb treatment. Anti-HMGB1 mAb attenuated the enhanced vasocontractile response to thrombin of the isolated BA from SAH rats and prevented activation of cerebrocortical microglia. Moreover, locomotor activity and weight loss recovery were also enhanced by anti-HMGB1 mAb administration. The vasocontractile response of the BA under SAH may be induced by events that are downstream of responses to HMGB1-induced inflammation and inhibited by anti-HMGB1 mAb. Anti-HMGB1 mAb treatment may provide a novel therapeutic strategy for DCV and early brain injury after SAH.

Epidemiology of Dural Arteriovenous Fistula in Japan: Analysis of Japanese Registry of Neuroendovascular Therapy (JR-NET2)

We developed the Japanese Registry of Neuroendovascular Therapy 2 (JR-NET2) database and used the information for a retrospective, nation-wide multicenter, observational study to clarify the clinical characteristics, current status of procedures, and outcome of patients treated by neuroendovascular therapy in Japan. In this report, we analyzed the clinical characteristics of dural arteriovenous fistulas (dAVFs) in the JR-NET2 database. All patients with dAVFs treated with endovascular therapy in 150 Japanese hospitals were included. Patient characteristics, clinical presentations, and imaging characteristics were analyzed. A total of 1,075 patients with dAVFs underwent 1,520 endovascular procedures. Of 1,075 patients, 45% were men and 55% were women. The mean age was 65 ± 13 years. The most frequent location of dAVFs was the cavernous sinus (43.6%), followed by the transverse-sigmoid sinus (TSS) (33.4%). Twelve percent of the patients had intracranial hemorrhage, 9% had venous infarction, and 3% had convulsion. The statistically significant independent risk factors of intracranial hemorrhage were TSS, superior sagittal sinus (SSS), tentorium, anterior cranial fossa, cranio-cervical junction, cortical venous reflux (CVR), and varix. Risk factors of venous infarction were age older than 60 years, male sex, TSS, SSS, and CVR. Risk factors of convulsion were male sex, SSS, and CVR. This is the largest nationwide report, to date, of the clinical characteristics of dAVFs treated by neuroendovascular therapy. CVR was a major risk factor of aggressive symptoms.