Effects of cilostazol on cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a multicenter prospective, randomized, open-label blinded end point trial.

OBJECT: Cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH) is a major cause of subsequent morbidity and mortality. Cilostazol, a selective inhibitor of phosphodiesterase 3, may attenuate cerebral vasospasm because of its antiplatelet and vasodilatory effects. A multicenter prospective randomized trial was conducted to investigate the effect of cilostazol on cerebral vasospasm. METHODS: Patients admitted with SAH caused by a ruptured anterior circulation aneurysm who were in Hunt and Kosnik Grades I to IV and were treated by clipping within 72 hours of SAH onset were enrolled at 7 neurosurgical sites in Japan. These patients were assigned to one of 2 groups: the usual therapy group (control group) or the add-on 100 mg cilostazol twice daily group (cilostazol group). The group assignments were done by a computer-generated randomization sequence. The primary study end point was the onset of symptomatic vasospasm. Secondary end points were the onset of angiographic vasospasm and new cerebral infarctions related to cerebral vasospasm, clinical outcome as assessed by the modified Rankin scale, and length of hospitalization. All end points were assessed for the intention-to-treat population. RESULTS: Between November 2009 and December 2010, 114 patients with SAH were treated by clipping within 72 hours from the onset of SAH and were screened. Five patients were excluded because no consent was given. Thus, 109 patients were randomly assigned to the cilostazol group (n = 54) or the control group (n = 55). Symptomatic vasospasm occurred in 13% (n = 7) of the cilostazol group and in 40% (n = 22) of the control group (p = 0.0021, Fisher exact test). The incidence of angiographic vasospasm was significantly lower in the cilostazol group than in the control group (50% vs 77%; p = 0.0055, Fisher exact test). Multiple logistic analyses demonstrated that nonuse of cilostazol is an independent factor for symptomatic and angiographic vasospasm. The incidence of new cerebral infarctions was also significantly lower in the cilostazol group than in the control group (11% vs 29%; p = 0.0304, Fisher exact test). Clinical outcomes at 1, 3, and 6 months after SAH in the cilostazol group were better than those in the control group, although a significant difference was not shown. There was also no significant difference in the length of hospitalization between the groups. No severe adverse event occurred during the study period. CONCLUSIONS: Oral administration of cilostazol is effective in preventing cerebral vasospasm with a low risk of severe adverse events. Clinical trial registration no. UMIN000004347, University Hospital Medical Information Network Clinical Trials Registry.

Intra-arterial injection fluorescein videoangiography in aneurysm surgery.

BACKGROUND: To visualize blood flow in the arteries and aneurysm during surgery, intravenous fluorescence videoangiography has been used. However, the image contrast with this procedure is diminished by repeated study because the dye remains for about 10 minutes after injection. OBJECTIVE: To determine the optimal dye concentration and to clarify the usefulness of fluorescein videoangiography by intra-arterial dye injection. METHODS: In the pilot study, fluorescein sodium dissolved at various concentrations was illuminated with excitation light, and fluorescence was detected by cameras. The fluorescence of 0.001% fluorescein sodium solution mixed with plasma at various concentrations was then examined. In 13 aneurysm patients, dye solution was administered through the catheter for intraoperative digital subtraction angiography. The intravenous injection method was also performed, and the findings were compared. RESULTS: Dye was clinically used at a concentration of 0.005% to 0.1% on the basis of the results of the pilot study. Fluorescence emission from the vessels and aneurysms was clearly observed by both methods; however, arterial injection provided brighter emission, resulting in clearer demonstration of the bloodstream than venous injection. Dye clearance was also quicker, which allowed repeat injections without delay. Dye filling in the aneurysm indicating incomplete occlusion was detected in 2 cases, and occlusion of the perforating artery was observed in 2 cases. CONCLUSION: Intra-arterial fluorescein videoangiography provides brighter and clearer imaging of blood flow with a smaller dose of dye than intravenous videoangiography. It can be repeated within a short time and is useful for detecting incomplete clipping or unexpected obstruction of arteries.

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

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

Quantification of thrombospondin-1 secretion and expression of alphavbeta3 and alpha3beta1 integrins and syndecan-1 as cell-surface receptors for thrombospondin-1 in malignant glioma cells.

Malignant glioma cells secrete thrombospondin-1 (TSP-1) which participates in the motility of glioma cells, and binds to cell surface alphavbeta3 and alpha3beta1 integrins, and syndecan-1. This study evaluated the amount of TSP-1 secretion from malignant glioma cells, and the expression of alphavbeta3 and alpha3beta1 integrins, and syndecan-1. The amounts of TSP-1 in the supernatants from 10 malignant glioma cell lines and eight non-glioma malignant tumor cell lines were measured by enzyme-linked immunosorbent assay. Expression of alphavbeta3 and alpha3beta1 integrins, and syndecan-1 were examined by flow cytometry. The amounts of TSP-1 secreted by malignant glioma cells were 43 to 2431 ng/l x 10(6) cells/24 h (mean +/- SD = 626 +/- 792). Seven of 10 glioma cell lines secreted more than 100 ng of TSP-1 and three of these cell lines secreted more than 1 microg. Seven of eight non-glioma cell lines secreted less than 100 ng of TSP-1. All glioma cell lines expressed alpha3beta1 integrin and syndecan-1, and seven of 10 glioma cell lines expressed alphavbeta3 integrin. Treatment of the glioma cell lines with TGF-beta2 did not change the expression of alphavbeta3 integrin. These results suggest that malignant glioma cells secrete high levels of TSP-1, which may be important in the migration of glioma cells via interactions with alphavbeta3 and alpha3beta1 integrins, and syndecan-1.