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.

Diagnostic value of the optic nerve sheath subarachnoid space in patients with intracranial hypotension syndrome.

OBJECT: The size of the subarachnoid space in the optic nerve sheath (ONS) on MR images is thought to reflect intracranial pressure. The diagnostic value of this space was investigated in patients with spontaneous intracranial hypotension (SIH) syndrome. METHODS: Coronal fat-saturated T2-weighted MRI of the orbit was performed in 15 patients with SIH fulfilling the diagnostic criteria for headache caused by low CSF pressure of the International Classification of Headache Disorders or the criteria for spontaneous spinal CSF leaks and intracranial hypotension. The size of the subarachnoid space in the ONS was measured in 2 slices behind the eyeballs. The images were compared before and after treatment. The CSF pressure was measured by lumbar puncture. RESULTS: Before treatment, the diameter of the ONS subarachnoid space ranged from 2.58 to 4.21 mm (mean 3.34 mm) and the thickness from 0 to 0.48 mm (mean 0.15 mm). Both measurements showed significant correlations with CSF opening pressure, and 8 patients had no CSF space before treatment. The size of CSF space increased in many patients after effective treatment. CONCLUSIONS: Disappearance of the CSF space in the ONS was frequently observed in patients with SIH. This characteristic finding may be useful in the diagnosis of SIH as well as in the evaluation of treatment effectiveness.

Bony carotid canal hypoplasia in patients with moyamoya disease.

OBJECT: The natural history of moyamoya disease is not well known. We have observed that the bony carotid canal is hypoplastic in patients with adult onset moyamoya disease. Bony carotid canal development should represent internal carotid artery (ICA) development, and may stop with the beginning of ICA stenosis. The purpose of this study was to determine the onset of moyamoya disease by measuring the bony carotid canal. METHODS: The normal diameter of the bony carotid canal was evaluated on 4-mm thick bone window CT scans of the skull base in 60 Japanese patients aged 20-80 years, who had minor head trauma or headache considered to be unrelated to the skull base or arterial systems. The relationship between age and bony carotid canal development was assessed in a second group of 50 patients aged 0-19 years, including 10 under 2 years, using CT scans with the same parameters. The diameter of the bony carotid canal in 17 Japanese patients with moyamoya disease was measured. RESULTS: The normal diameter in adults was 5.27 +/- 0.62 mm (mean +/- SD). The bony carotid canal developed rapidly before approximately 2 years of age. After fusion of the bony suture, the bony carotid canal developed slowly. The mean diameter of the bony carotid canal was 3.31 +/- 0.44 mm in 11 adult patients with adult-onset moyamoya disease. According to the apparent curve of bony carotid canal development, ICA stenosis was assumed to start in early childhood. CONCLUSIONS: Our findings suggest that most cases of Asian moyamoya disease may arise in childhood and that many Asian adult patients with moyamoya disease may develop occlusive vasculopathy in childhood.

Current usage of three-dimensional computed tomography angiography for the diagnosis and treatment of ruptured cerebral aneurysms.

Our previous study suggested that 3D-CT angiography could replace digital subtraction (DS) angiography in most cases of ruptured cerebral aneurysms, especially in the anterior circulation. This study reviewed our further experience. One hundred and fifty patients with ruptured cerebral aneurysms were treated between November 1998 and March 2002. Only 3D-CT angiography was used for the preoperative work-up study in patients with anterior circulation aneurysms, unless the attending neurosurgeons agreed that DS angiography was required. Both 3D-CT angiography and DS angiography were performed in patients with posterior circulation aneurysms, except for recent cases that were possibly treated with 3D-CT angiography alone. One hundred sixteen (84%) of 138 patients with ruptured anterior circulation aneurysms underwent surgical treatment, but additional DS angiography was required in 22 cases (16%). Only two recent patients were treated surgically with 3D-CT angiography alone in 12 patients with posterior circulation aneurysms. Most patients with ruptured anterior circulation aneurysms could be treated successfully after 3D-CT angiography alone. However, additional DS angiography is still necessary in atypical cases. 3D-CT angiography may be limited to complementary use in patients with ruptured posterior circulation aneurysms.

Late recurrence of subarachnoid hemorrhage due to regrowth of aneurysm after neck clipping surgery.

Late recurrence of subarachnoid hemorrhage (SAH) due to regrowth of aneurysm after neck clipping surgery occurred in four patients. Two patients underwent surgical treatment, and two patients received endovascular treatment. Endovascular treatment was successful in one case, but emergent surgery was necessary for the other case because of possible pseudoaneurysm formation. Postoperative course of all patients was excellent. Late recurrence of SAH can occur even after complete clipping, and further treatment should be considered.

Molecular mechanisms of cardiostimulatory effects of sildenafil.

To better understand the molecular mechanisms of the previously described cardiostimulatory action of the phosphodiesterase type-5 (PDE5) inhibitor sildenafil, we first evaluated its effects on cyclic AMP level in the canine ventricular membrane preparation. Sildenafil (10 micromol/L) significantly increased the net cyclic AMP production rate, the potency of which was similar to that of 3-isobutyl-1-methylxanthine (IBMX). Next, we assessed the inhibitory effect of sildenafil on PDE of bovine heart. Sildenafil (> or = 1 micromol/L) as well as IBMX significantly decreased the cyclic AMP hydrolyzing speed of PDE. These results suggest that a supra-therapeutic concentration of sildenafil may directly inhibit cyclic AMP hydrolyzing PDEs in the heart, although indirect inhibition of PDE3 via the "cross-talk" pathway cannot be totally excluded.