Introduction
Subarachnoid hemorrhage (SAH) is the most frequently caused by intracranial aneurysmal rupture.15) However, about 15% to 20% of patients with SAH have negative findings on initial 4-vessel cerebral angiography.24) These patients with SAH of unknown etiology are generally considered to have a good prognosis, especially perimesencephalic non-aneurysmal SAH.16)19)22) Several causes of initial negative angiogram SAH have been reported, such as vasospasm, hematoma or brain swelling.10) Some posterior fossa aneurysms may show only perimesencephalic SAH.18) Therefore it is necessary to repeat angiography for diagnosis, although the value of repeat angiography remains controversial.17)
This study focused on the incidence of patients with SAH of initial negative angiography, the efficacy of repeat angiography and the usefulness of angiography. Additional objective was to determine the relationship between the hidden aneurysm and initial CT pattern, in terms of amount and distribution of SAH.

Materials and methods
From March 2003 to December 2007, 679 patients with spontaneous SAH were admitted to our institute. The diagnosis was determined by either computerized tomography (CT) scan or lumbar puncture. Of the 679 patients, 593 (87%) underwent transfemoral catheter cerebral angiography (TFCA) with multiple views. Eighty-three (14%) out of 593 patients were found to have SAH without any intracranial identifiable causes (Fig. 1). The amount of subarachnoid blood was classified following Fisher’s grading system and the location of blood was classified into 1) diffuse, with or without local dominance, 2) perimesencephalic cistern, 3) Sylvian fissure, 4) interhemispheric fissure, 5) ventricle or other locations. In 83 patients, the interval between the onset of symptoms and the initial TFCA study ranged from 0 to 15 days (1.9±2.7, mean±standard deviation (SD)). A repeat angiography was performed on 67 of these 83 patients, between 1 to 27 days (8.5±2.7, mean±SD) via CT angiography (39 patients), TFCA (26 patients) and magnetic resonance (MR) angiography (2 patients). The remaining 16 patients did not undergo repeat angiography because of their severe clinical state, refuse of further evaluation or transfer to other institute. These 67 patients were subsequently divided into two groups. In group I, 10 patients showed aneurysms on repeated angiographic study and they underwent operation, except 1 patient, because of refusal of operation; in group II, 57 patients did not reveal any identifiable angiographic findings, even on repeat angiography.
For analysis of statistical variables and comparison about detecting the aneurysm in each group, ANOVA and Tukey’s honestly significant difference were used. The statistical significance level was set at a P value less than 0.05.
 Results
Clinical presentation
The age of the patients ranged from 19 to 79 years with a mean of 53.7 years. There was no sex predilection (M/F=41/42). The most common presentation was sudden headache, occasionally accompanied by neck stiffness and vomiting.

Angiography
The mean timing of repeat angiography was 8.5±6.0 days after ictus, and CTA was applied in the earlier period than TFCA. CTA was performed at 6.2±4.4 days after ictus, whereas TFCA was done at 12.2±6.2 days after ictus. Ten (15%) out of 67 patients revealed aneurysms which were not seen on initial angiography (Group I): 3 at the anterior communicating artery, 2 at the anterior cerebral artery, 3 at the internal carotid artery, 1 at the middle cerebral artery and one at the vertebral artery. Three out of these 10 patients were detected by CT angiography and the others were by TFCA. These group I patients were recommended neurosurgical treatment and 9 of them underwent open craniotomy, except one patient, who showed poor neurological state due to rebleeding. The nine operated patients showed good outcome, without neurologic deficits (Table 1).

CT findings
All patients with suspected SAH were evaluated by CT scans. Clinical grading of patients was performed using Hunt and Hess scales at the time of admission.13) The amount of subarachnoid blood was classified into four groups, according to the Fisher's grading system.8) Of the 67 patients, 7 cases whose initial CT scans were taken later than 3 days after ictus were excluded. Of the 60 patients, 3 were in Fisher’s grade 1, 19 were in grade 2, 31 were in grade 3, and 7 were in grade 4 (Table 2). In the Group I patients, one patient was in Fisher’s grade 2 (5%), 8 were in grade 3 (26%), and 1 was in grade 4 (14%). No aneurysm was detected on the repeated angiography in three patients with Fisher’s grade 1 (P=0.05) (Table 2). Thirty-eight (63%) out of 60 patients showed diffuse blood distribution and 22 patients (37%) showed local distribution. On the repeated angiography, 9 (24%) out of 38 patients with diffuse blood distribution revealed aneurysms, whereas only one patient with local blood distribution showed aneurysm (P=0.05) (Table 3).
Discussion
The value of repeated angiography in SAH patients with initially negative angiography has been a controversial issue. Forster et al. suggested one angiogram to be sufficient.9) However, current studies showed that the rate of false negative initial angiography varied considerably (1.7~17.8%).15)16) In our study, the false negative rate of initial angiography was 13%. Factors involved in the failure to detect an aneurysm on the initial angiography were proposed. Formation of thrombosis in the aneurysmal sac appears to be the most probable reason for initial negative angiogram. Turbulance of blood flow and narrowing of the aneurysmal orifice may be factors for formation of an intra-aneurysmal thrombus.15) Spasms at the aneurysmal orifice and the feeding artery cause changes in circulation and may lead to disturbance in laminar blood flow, which can in turn influence aneurysm flow dynamics, leading to thrombosis.17) Another factor could be misreading of angiographic findings using standard neuroradiologic techniques; therefore, multiple supplemental projections are needed to differentiate too small aneurysm or adjacent arteries.
Iwanaga et al.15) and Di Lorenzo et al.6) demonstrated the close relationship between considerable blood amount and detection rate of aneurysms, also blood distribution pattern of SAH patients and detection rate of aneurysms with negative initial angiograms for aneurysm. In our study, 31 out of 60 patients had thick layer of blood amount according to Fischer's grading system III and 25% of these patients revealed an aneurysm on repeated angiography. 38 out of 60 patients showed diffuse blood distribution. In 23% of 38 patients with diffuse blood distribution, repetition of angiography revealed an aneurysm and 5 patients suffered from anterior circulation aneurysm (A-com and ACA).
In 1985, van Gijn et al.25) reported on a subset of patients with SAH whose angiograms were negative, in whom the initial CT scan demonstrated that the blood was primarily limited to the perimesencephalic cisterns and the clinical course of this group was showing good outcome. The incidence of rebleeding was significantly lower in patients with negative angiographic SAH than in those with ruptured aneurysm.2)14)23) In our study, only one patient had rebleeding in Group II. In most series, the incidence of rebleeding ranged from 0 to 5%.4)20) Although rebleeding occurred, the outcome was better than in patients with aneurysmal SAH.5)
Because of the risk of rebleeding, vasospasm and other complications due to ruptured aneurysm, hidden aneurysms should be identified as early as possible. Kaim et al.17) documented that repeat angiography plays an important role in defining the site of an initially occult aneurysm, and should therefore be performed in all cases of unexplained SAH patients. We performed repeated angiogram in 81% of 83 initially negative angiogram patients via TFCA, CT angiogram and MR angiogram. The mean timing of repeated angiogram was 6.2±4.4 days after ictus on CT angiography and 12.2±6.2 days after ictus on TFCA. In the detection of cerebral aneurysms, the sensitivity and specificity of CT angiogram have been found to vary, ranging from 77 to 97% and from 50 to 100%, respectively.1)3)12)21) Although CT angiography is less invasive than TFCA, whether it can be the gold standard for detection of aneurysms remains unclear.1)7) In another study, Hashimoto et al. indicated that spiral CT angiography was useful in the detection of cerebral aneurysms in patients with SAH in whom initial angiography revealed no diagnostic findings.11) In a previous study, Rogg et al. evaluated the benefit of MR imaging for angiography negative SAH and found relevant abnormality in 14% of 71 patients and MR imaging appeared to be most useful for patients with CT negative, but lumbar puncture positive SAH.23) In our study, only two patients underwent MR angiography for second evaluation and they did not show any abnormal findings.
Conclusions
Repeated angiography revealed 15% of ruptured aneurysms in SAH with negative initial angiography. Our study concludes that the bleeding amount or distribution of SAH may suggest the location of the bleeding origin. Therefore, if CT scans show thick subarachnoid blood or diffuse blood distribution, repeated angiographic study should be performed. At that time, CT angiography could be applied in the earlier period, and was useful to identify hidden aneurysms.
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