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Size of ruptured intracranial saccular aneurysms in patients in Izumo City, Japan
Aneurysm
Size of ruptured intracranial saccular aneurysms in patients in Izumo City, Japan Tetsuji Inagawa MD, PhD⁎ Department of Neurosurgery, Shimane Prefectural Central Hospital, Izumo, Japan Received 2 May 2009; accepted 2 July 2009
Abstract
Background: A community-based study was conducted to evaluate the factors related to the size of ruptured aneurysms and the effects of aneurysm size on clinical features. Methods: Data from 358 patients with subarachnoid hemorrhage (SAH) treated between 1980 and 1998 in Izumo, Japan, were reviewed. In 285 of these patients, the sizes of the ruptured aneurysms were determined. Results: Aneurysm diameter was less than 5 mm in 68 patients, at least 5 to less than 10 mm in 137 patients, and 10 mm or more in 80 patients. Aneurysm size tended to increase with patient age. Age (≥60 years of age) and cigarette smoking were independently associated with aneurysms of 5 mm or more in diameter. Multiple aneurysms were positively and anterior cerebral artery aneurysms were inversely related to aneurysms of 10 mm or more in diameter. The larger the aneurysm, the worse was the World Federation of Neurosurgical Societies grade. The risk of rebleeding was higher in patients with larger (≥10 mm) aneurysms than in those with smaller (b10 mm) aneurysms. The incidences of diffuse severe SAH on computed tomographic scans in patients with SAH alone, symptomatic vasospasm, and hydrocephalus were higher in patients with larger (≥5 mm) aneurysms than in those with smaller (b5 mm) aneurysms. The larger the aneurysm, the worse was either functional outcome or the 6-month and 2-year survival rates. Conclusion: Age, cigarette smoking, multiple aneurysms, and aneurysm site appear to be related to the size of ruptured aneurysms. Patients with larger aneurysms seem to have a worse clinical condition and more severe SAH, resulting in higher incidences of rebleeding, symptomatic vasospasm and hydrocephalus, and a worse outcome. © 2010 Elsevier Inc. All rights reserved.
Keywords:
Aneurysm size; Cerebral aneurysm; Epidemiological study; Subarachnoid hemorrhage
1. Introduction Despite the recent advances in the management of ruptured intracranial aneurysm, the prognosis remains Abbreviations: ACA, anterior cerebral artery; CT, computed tomography; GCS, Glasgow Coma Scale; ICA, internal carotid artery; ICH, intracerebral hemorrhage; IVH, intraventricular hemorrhage; MCA, middle cerebral artery; SAH, subarachnoid hemorrhage; SDH, subdural hematoma; VBA, vertebrobasilar artery; WFNS, World Federation of Neurosurgical Societies. ⁎ Department of Neurosurgery, Araki Neurosurgical Hospital, Hiroshima, Hiroshima 733-0821, Japan. Tel.: +81 082 272 1114; fax: +81 082 272 7048. E-mail address: [email protected].
unsatisfactory. In Izumo City, Japan, the overall 6-month case fatality rate after aneurysmal SAH was 39%, and 13% of patients remained dependent on help [12]. The size of an intracranial aneurysm is an important prognostic factor for rupture; large aneurysms have a higher risk of rupture. After rupture, the size of the aneurysm lumen, that is, the angiographic aneurysm size, decreases due to formation of an intraaneurysm thrombus, which adheres to the inner wall at the point of rupture [8]. Various studies have investigated whether age [14,15,21,29,30,32,33,36,43,47] and some cerebrovascular risk factors [23,24,30,33,35-37,39], including hypertension and smoking, are related to the size of aneurysms, or whether aneurysm size affects the clinical
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features such as clinical condition [16,36,38-40,44], rebleeding [16,17,26], vasospasm [31,38,44], hydrocephalus [42,44,46], and outcome [27,36,38,39,41,44,47]. However, the results obtained have not necessarily been consistent, and some have been conflicting. These inconsistencies may be due in part to patient materials that have not been population based. The best data can be obtained from community-based studies that include all incident cases of disease, regardless of the age and clinical condition of the patient. Some population-based data on SAH are available, but no previous population-based studies have reported aneurysm features, including size and site. An ideal study would be a community-based one in which all diagnoses are systematically verified by neuroimaging. In the present study based in Izumo, I investigated risk factors related to the size of aneurysms that were confirmed by angiography, surgery and/or autopsy, and the effects of aneurysm size on clinical features.
2. Materials and methods Izumo City is located in the western part of Japan, covering a rural area of approximately 175 km2 and has 80 000 inhabitants. There is no heavy industry, and the social and demographic composition is relatively stable. Izumo has 4 hospitals, and CT scanning is an available procedure at each of them. Because 2 hospitals have both neurosurgical and neurologic departments and are designated emergency centers, all patients with verified or suspected SAH, even if moribund and regardless of age or condition, are immediately referred to the neurosurgical department of either hospital [9,11,12]. On admission, each patient's clinical condition was evaluated using the GCS [45]. To allow comparison of the patients in the present study with those in previously published studies, the clinical condition was classified according to the WFNS scale [3], which is based on the GCS score. Even if a patient was dead by the time of referral or was moribund on admission, we attempted to perform CT scanning studies whenever possible to confirm SAH, and clinical information was collected from relatives. In addition, I reviewed the death certificates and analyzed the records of those suspected of having died of hemorrhagic stroke [7,10]. Data were collected from the records of the 4 hospitals and the patients' death certificates [7-12]. Patients who died before hospital admission or who had a cardiorespiratory arrest on arrival were included in grade V. During the 19-year period between 1980 and 1998, aneurysmal SAH was diagnosed in 358 patients [9,12]. Five cases were picked up in the hospital charts after review of the death certificates. The other cases, however, were ascertained from the hospital charts without the need to review death certificates. The exact location of the ruptured aneurysm was confirmed in 291 (81%) of the 358 patients, excluding 1 patient with a dissecting aneurysm of the ACA. The size of the aneurysm was determined in 285 (98%) of the
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291 patients with saccular aneurysms—53 by angiography, 202 by angiography and surgery, 21 by angiography and autopsy, 6 by angiography, surgery and autopsy, 2 by autopsy, and 1 by CT angiography. Of the 6 aneurysms of which size was unknown, 2 were located on the ACA, 2 on the MCA, 1 on the ICA, and 1 on the basilar artery. The aneurysms were divided into 3 groups according to maximum diameter: less than 5 mm, at least 5 to less than 10 mm, and 10 mm or more. I collected data on the following risk factors: hypertension, diabetes mellitus, heart disease (valvular disease, coronary heart disease, and myocardial infarction), cigarette smoking, alcohol consumption, and serum total cholesterol level. Hypertension was defined as a history of the disorder, regardless of treatment with antihypertension medication. Information on diabetes and heart disease was based on medical history. Serum total cholesterol levels were obtained on admission to hospital. Details of the methods used for collecting the data and definitions of risk factors have been given elsewhere [11,13]. The diagnosis of rebleeding was described in our earlier studies in detail [6,17]. Episodes of rebleeding occurred in 81 (28%) of 285 patients: 21 patients before admission, 59 patients after admission, and 1 patient both before and after admission. Of these patients, 42 (52%) rebled within 6 hours. Aneurysmal SAH was classified by CT scan performed on admission into 4 anatomical types: SAH alone, ICH, IVH, and SDH [17]. In patients with SAH alone, SAH on the CT scan was graded from I to IV [5,20]. In this SAH grading, when SAH on CT scan was slight or moderate, it was classified as grade I or II, respectively. When a clot was severe and densely packed over a limited area, it was classified as grade III. If it was severe and densely packed over a diffuse area, it was classified as grade IV. After excluding 22 patients who had rebleeding before admission, the association between aneurysm size and the type of hemorrhage on the admission CT scan was evaluated in 263 patients. With respect to the association between aneurysm size and SAH grade in patients with SAH alone, analyses were restricted to the 155 patients who had no rebleeding before admission and were admitted within 24 hours after SAH. In the present study, clipping of ruptured aneurysms was defined as surgery; however, ventricular drainage alone and coil embolization for ruptured aneurysms were not. Symptomatic vasospasm was evaluated according to the criteria of Inagawa [5] and Inagawa et al [20]. Hydrocephalus was considered present if a ventriculoperitoneal shunt was placed during hospitalization. Symptomatic vasospasm and hydrocephalus were evaluated for 195 patients who underwent surgery and who had WFNS grades I to IV preoperatively because these features are difficult to assess if the patient's clinical condition is extremely poor. After discharge, the patients underwent a follow-up review by a variety of methods, including personal consultation, telephone interview, and written correspondence. Only 2
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Table 1 Baseline characteristics of 285 patients with ruptured cerebral aneurysms Category
P
Size of ruptured aneurysm (mm)
No. of patients Women Age (y) b60 ≥60 to b70 ≥70 Mean ± SD Site of ruptured aneurysm ACA ICA MCA VBA Multiple aneurysms Hypertension Present Absent Diabetes mellitus Present Absent Heart disease Present Absent Cigarette smoking Current regular & former smoker Nonsmoker Alcohol intake Daily drinking Occasional or no drinking Total cholesterol (mg/dL) ≥220 b220
b5
≥5 to b10
≥10
68 44 (65)
137 70 (51)
80 50 (63)
38 (56) 20 (29) 10 (15) 56.9 ± 12.6
60 (44) 33 (24) 44 (32) 62.5 ± 12.1
34 (43) 20 (25) 26 (33) 63.0 ± 13.1
.1020 .0386
Total cases
285 164 (58) 132 (46) 73 (26) 80 (28) 61.3 ± 12.7
.0101 38 10 16 4 18
(56) (15) (24) (6) (26)
64 (47) 30 (22) 35 (26) 8 (6) 29 (21)
21 (26) 29 (36) 24 (30) 6 (8) 30 (38)
34 (51) 33 (49)
67 (50) 67 (50)
39 (50) 39 (50)
3 (5) 61 (95)
3 (2) 126 (98)
2 (3) 63 (97)
2 (3) 62 (97)
14 (11) 116 (89)
4 (6) 61 (94)
16 (26) 45 (74)
60 (47) 69 (53)
26 (35) 49 (65)
17 (28) 44 (72)
48 (38) 80 (63)
16 (22) 58 (78)
16 (29) 40 (71)
25 (21) 92 (79)
17 (27) 45 (73)
.0326 .9943
123 (43) 69 (24) 75 (26) 18 (6) 77 (27) 140 (50) 139 (50)
.6721 8 (3) 250 (97) .1483 20 (8) 239 (92) .0198 102 (38) 163 (62) .0532 81 (31) 182 (69) .4973 58 (25) 177 (75)
VBA indicates vertebrobasilar artery. Values represent the number (%).
patients were lost to follow-up review in the 2 years after the initial SAH. The outcome at 6 months after SAH was classified according to the Glasgow Outcome Scale [22]. The χ2 test, Fisher exact test, or Spearman correlation coefficient by rank test was used for statistical analysis. I performed multiple logistic regression analysis to determine the variables associated with developing large aneurysms. For this analysis, the 3 categories of aneurysm size were combined to form 2 categories in 2 ways; one was division into less than 5 mm in diameter and 5 mm or more in diameter, and the other was division into less than 10 mm in diameter and 10 mm or more in diameter. The variables assessed were age, sex, site of ruptured aneurysms, single or multiple lesions, history of hypertension, diabetes mellitus,
heart disease, cigarette smoking, alcohol consumption, and total cholesterol on admission. The possibility of survival was estimated by the Kaplan-Meier product-limit method [25], and the curves for different groups were compared by the log-rank test. Multiple logistic regression analysis was performed to determine the variables associated with 6month case fatality, and the Cox proportional hazards analysis [2] was used to identify variables that predicted 2year survival. The variables assessed were age, sex, hours between onset and admission, WFNS grade on admission, site of ruptured aneurysms, rebleeding, any evidence of a concomitant hematoma on the CT scan, and maximum aneurysm diameter. Statistical analysis was performed using commercially available software (JMP Statistical Analysis
Table 2 Independent risk factors associated with large aneurysms, using multiple logistic regression analysis Size of ruptured aneurysm (mm) Variable
Categories
Odds ratio (95% confidence interval) P
≥5
≥60 or b60 y Current regular & former smoker or nonsmokers Multiple or single ACA aneurysm or other sites
3.3 (1.6-7.4) 5.5 (1.9-17.6) 2.0 (1.0-4.0) 0.4 (0.2-0.8)
≥10
86
Age Cigarette smoking Multiple aneurysms Site of ruptured aneurysms
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.0023 .0026 .0376 .0122
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Table 3 Clinical characteristics and CT findings at admission in 285 patients with ruptured cerebral aneurysms Category
P
Size of ruptured aneurysm (mm)
No. of patients Admission within 6 h after SAH WFNS grade on admission I II or III IV V Rebleeding Type of hemorrhage on CT scan a SAH alone ICH IVH ICH + IVH SDH SAH grade in patients with SAH alone b I II III IV Surgery Preoperative WFNS grade I II or III IV V
b5
≥5 to b10
≥10
68 51 (75)
137 100 (73)
80 60 (75)
43 (63) 5 (7) 11 (16) 9 (13) 16 (24)
62 22 27 26 32
(45) (16) (20) (19) (23)
21 10 21 28 33
.9766 b.0001
(26) (13) (26) (35) (41)
51 (78) 6 (9) 1 (2) 7 (11) 0 (0)
101 (81) 11 (9) 6 (5) 4 (3) 2 (2)
53 (72) 5 (7) 8 (11) 7 (9) 1 (1)
9 (24) 11 (30) 12 (32) 5 (14) 55 (81)
18 (23) 16 (20) 21 (26) 25 (31) 106 (77)
7 10 11 10 47
(18) (26) (29) (26) (59)
16 13 11 7
(34) (28) (23) (15)
Total cases
.0111 .1505
285 211 (74) 126 (44) 37 (13) 59 (21) 63 (22) 81 (28) 205 (78) 22 (9) 15 (6) 18 (7) 3 (1)
.2676
34 (62) 11 (20) 8 (15) 2 (4)
52 22 28 4
(49) (21) (26) (4)
.0028 .0027
34 (22) 37 (24) 44 (28) 40 (26) 208 (73) 102 (49) 46 (22) 47 (23) 13 (6)
Values represent the number (%). a Analyses were performed on 263 patients who had no rebleeding before admission. b Analyses were performed on 155 patients who had no rebleeding before admission and were admitted within 24 hours after SAH. The percentages of SAH grades I to III and IV are 86% and 14% for patients with aneurysms less than 5 mm in diameter, respectively, and 70% and 30% for those with aneurysms of 5 mm or more, respectively (P = .0364).
Program [version 3.0], SAS Institute Inc, Cary, NC). Differences at P b .05 were considered to be significant. 3. Results 3.1. Factors related to aneurysm size The aneurysms were less than 5 mm in diameter in 68 patients (24%), at least 5 to less than 10 mm in 137 patients
(48%), and 10 mm or more in 80 patients (28%) (Table 1). Of 285 aneurysms, 13 (5%) were giant (≥25 mm) aneurysms. The ratio of women to men did not differ significantly among the 3 size groups. The size of ruptured aneurysms tended to increase with age. The frequency of ACA aneurysms was higher among smaller aneurysms, whereas ICA and MCA aneurysms were more common among larger aneurysms. The frequency of multiple aneurysms was higher in patients with aneurysms ≥10 mm in diameter (38%, 30 of 80 patients)
Table 4 Vasospasm and shunt-dependent hydrocephalus in 195 patients who underwent surgery and who had preoperative WFNS grades I to IV Category
No. of patients Vasospasm Permanent vasospasm Death from vasospasm Transient vasospasm Absent Shunt-dependent hydrocephalus Present Absent
P
Size of ruptured aneurysm (mm) b5
≥5 to b10
≥10
53
102
40
Total cases 195
.0815 4 (8) 1 4 (8) 45 (85)
17 (17) 3 15 (15) 70 (69)
7 (18) 1 5 (13) 28 (70)
21 (40) 32 (60)
66 (65) 36 (35)
19 (48) 21 (53)
28 (14) 5 24 (12) 143 (73) .0074 106 (54) 89 (46)
Values represent the number (%). The incidences of symptomatic (permanent and transient) vasospasm are 15% for patients with aneurysms of less than 5 mm in diameter and 31% for those with aneurysms of 5 mm or more (P = .0255), and the incidences of hydrocephalus are 40% and 60%, respectively (P = .0116).
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Table 5 Glasgow Outcome Scale scores at 6 months after onset in 285 patients with ruptured cerebral aneurysms Category
Surgical outcome Good recovery Moderate disability Severe disability Vegetative state Dead Management outcome Good recovery Moderate disability Severe disability Vegetative state Dead
Size of ruptured aneurysm (mm) b5
≥5 to b10
≥10
39 (71) 8 (15) 4 (7) 2 (4) 2 (4)
65 (61) 12 (11) 18 (17) 5 (5) 6 (6)
27 4 5 5 6
(57) (9) (11) (11) (13)
39 (57) 8 (12) 4 (6) 3 (4) 14 (21)
65 (47) 13 (9) 18 (13) 6 (4) 35 (26)
29 4 7 5 35
(36) (5) (9) (6) (44)
P
Total cases
.0534 131 (63) 24 (12) 27 (13) 12 (6) 14 (7) .0010 133 (47) 25 (9) 29 (10) 14 (5) 84 (29)
Values represent the number (%).
compared with those with aneurysms of less than 10 mm (23%; 47/205 patients) (P = .0127). Aneurysm size was associated with cigarette smoking but not with other risk factors. The proportion of smokers was 26% (16/61 patients) among patients with aneurysms of less than 5 mm in diameter and 42% (86/204 patients) among those with aneurysms of 5 mm or more (P = .0248). Age (≥60 years of age) and cigarette smoking were independently associated with aneurysms of 5 mm or more in diameter, and multiple aneurysms were positively related to those 10 mm or more in diameter (Table 2). In contrast, ACA aneurysms were inversely associated aneurysms of 10 mm or more in diameter. 3.2. Effects of aneurysm size on clinical features Of the 285 patients with ruptured aneurysms, 211 (74%) were admitted within 6 hours after onset (Table 3). The larger
the aneurysm, the worse was the WFNS grade on admission. The risk of rebleeding was approximately 2-fold in patents with aneurysms of 10 mm or more in diameter compared with those with aneurysms of less than 10 mm (P = .0027). The rebleeding rate within 6 hours after initial SAH was also significantly higher in patients with aneurysms of 10 mm or more in diameter (23%, 18/80 patients) than in those with aneurysms of less than 10 mm (12%, 24/205 patients) (P = .0209). There was no significant difference in the type of hemorrhage on CT scan among the 3 size groups. With respect to the association between aneurysm size and SAH grade in patients with SAH alone, there was also no significant difference among the 3 size groups. However, the percentage of SAH grade IV was significantly higher in patients with aneurysms of 5 mm or more in diameter (30%, 35/118 patients) compared with those with aneurysms of less than 5 mm (14%, 5/37 patients) (P = .0364). Surgery was performed on 208 (73%) patients. Patients with larger aneurysms tended to be operated on less frequently, and the larger the aneurysm, the worse was the preoperative grade. The main reason for withholding surgery was poor patient condition because of the direct effect of the aneurysm rupture itself, followed by rebleeding. The percentages of patients who were not operated on because of their poor condition were 9% (6/68 patients) among those with aneurysms of less than 5 mm in diameter, 13% (18/137 patients) among those with aneurysms of at least 5 to less than 10 mm in diameter, and 21% (17/80 patients) among those with aneurysms of 10 mm or more in diameter. Of the 77 patients who did not undergo surgery, 7 were treated with coil embolization for ruptured aneurysms: these included 2 aneurysms of less than 5 mm in diameter, 2 aneurysms of at least 5 to less than 10 mm in diameter, and 3 aneurysms of 10 mm or more in diameter. The main reasons for endovascular therapy included the advanced age of the patient and/or poor clinical status at admission: 1 patient in grade IV and 6 in grade V.
Fig. 1. Graphs showing comparisons of 2-year survival curves for patients with ruptured aneurysms in relation to aneurysm size. Left, Operative patients. Right, Management patients.
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Table 6 Survival P values in multivariate analysis Variable
Sex Age (y) Hours between onset and admission WFNS grade on admission Rebleeding Site of ruptured aneurysms Concomitant hematoma on CT scan c Size of ruptured aneurysms (mm) a b c
Categories
Female or male b60 or ≥60 Within or after 6 h I-III or IV-V Presence or absence ACA, ICA, MCA, or VBA Presence or absence b5, ≥5 to b10, or ≥10
6-month survival a
2-y survival b
Size of ruptured aneurysm (mm)
Size of ruptured aneurysm (mm)
b5
≥5 to b10 ≥10
0.1149 0.1067 0.1538 0.0347 0.1386 0.9631 0.9828
0.5932 0.2306 0.4465 0.0004 0.9620 0.4665 0.8310
Total cases b5
0.1235 0.1406 0.5710 0.1553 0.0398 0.0354 0.0022 b0.0001 0.0019 0.0004 0.0727 0.0020 0.1970 0.3600 0.4533
0.0008 0.0120 0.5427 0.0057 0.0012 0.4281 0.5430
≥5 to b10 ≥10 0.4662 0.1130 0.6925 0.0003 0.4998 0.5001 0.5917
Total cases
0.2153 0.0168 0.3676 0.0169 0.1486 0.1712 0.0011 b0.0001 0.0050 b0.0001 0.2502 0.0083 0.3942 0.7870 0.1556
Statistical analyses were performed using the multiple logistic regression analysis. Statistical analyses were performed using the Cox proportional hazards model. Intracerebral hemorrhage, massive IVH, or SDH.
The number of patients who underwent surgery and who had preoperative WFNS grades I to IV was 195 (Table 4). Of these patients, 52 (27%) had symptomatic vasospasm, including permanent and transient vasospasms, and 106 (54%) developed shunt-dependent hydrocephalus. When dividing patients into those with aneurysms of less than 5 mm in diameter and those with aneurysms of 5 mm or more in diameter, symptomatic vasospasm was observed in 15% (8/53 patients) and 31% (44/142 patients), respectively (P = .0255), and hydrocephalus occurred in 40% (21/53 patients) and 60% (85/142 patients), respectively (P = .0116). The larger the aneurysm, the worse both surgical and management outcomes became (Table 5). However, in patients who underwent surgery, the differences among the 3 size groups did not reach statistical significance. Furthermore, when stratified by WFNS grade, there were no evident significant differences in surgical or management outcome among the 3 groups. The 6-month case fatality rates after SAH were 7% for patients who underwent surgery and 29% for patients overall, managed by a variety of methods. The leading cause of death was the direct effect of aneurysm rupture itself. The percentages of patients who died of such a direct effect were 7% (5/68 patients) among those with aneurysms of less than 5 mm in diameter, 14% (19/137 patients) among those with aneurysms of at least 5 to less than 10 mm in diameter, and 26% (21/80 patients) among those with aneurysms of 10 mm or more in diameter. When comparing the 2-year survival curves among the 3 size groups, there were significant differences both in patients who were treated surgically and in patients overall who were managed using a variety of methods (Fig. 1). The larger the aneurysm, the worse the survival curves became. The differences were less significant in patients who were treated surgically than in those who were managed overall. In patients who were treated surgically, the cumulative 2-year survival rates were 93% for those with aneurysms of less than 5 mm in diameter, 89% for those with aneurysms of at least 5 to less than 10 mm in diameter, 74% for those with aneurysms of 10 mm or more in diameter, and 87% as a
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whole, whereas in patients who were managed overall, these rates were 76%, 70%, 48%, and 65%, respectively. When all patients were included, the most important predictors of both the 6-month and 2-year survival rates, in order of decreasing reliability, were WFNS grade on admission, rebleeding, and the site of the ruptured aneurysm (Table 6). Sex and age were also significant predictors of the 2-year survival rate, but they were not significant predictors of the 6-month case fatality rate. In patients with aneurysms of less than 5 mm in diameter, only WFNS grade on admission was a significant predictor of 6-month survival, whereas significant predictors of 2-year survival, in order of decreasing reliability, were sex, rebleeding, WFNS grade on admission, and age. In patients with aneurysms of at least 5 to less than 10 mm in diameter, only WFNS grade on admission was a significant predictor of both the 6-month and 2-year survival rates. In patients with aneurysms of 10 mm or more in diameter, WFNS grade on admission and rebleeding were significant predictors of both the 6-month and 2-year survival rates, and the length of time between onset and admission was also a significant predictor of 6-month survival.
4. Discussion 4.1. Factors related to aneurysm size In published studies, it has been controversial whether the size of ruptured aneurysms differs with patient age. Most hospital-based studies have shown that the size of ruptured aneurysms did not increase with age [1,14,21,29,33,36,47]. In contrast, according to the Cooperative Study of Intracranial Aneurysms [30], the size of ruptured aneurysms tended to increase with age. In autopsy studies, Sugai and Shoji [43] suggested that large aneurysms were more common in the elderly, whereas Inagawa and Hirano [15] and McCormick and Acosta-Rua [32] found no relationship between patient age and aneurysm size. In the present study, aneurysms tended to be larger in the older age groups. When
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considering that the incidence of aneurysmal SAH increases with increasing age [7,9] and atherosclerosis of the circle of Willis is more prominent in older patients [16], aneurysms in the elderly may not rupture as easily as those in younger patients. This may be one of the reasons why there was a relationship between aneurysm size and age. A limitation of this study was that the exact size of the ruptured aneurysm was not determined in 73 (20%) of the 358 patients with aneurysmal SAH, mainly because of their poor clinical condition and/or very old age. When taking into account the rapid increase in the number of very elderly people in most countries, it is vitally important to obtain reliable information about elderly patients. The size of the ruptured aneurysm did not differ significantly between women and men, similar to findings reported previously [28,33,36,39]. In the present study, ruptured ACA aneurysms were smaller than ICA or MCA aneurysms. Earlier studies also found that ruptured aneurysms located in the ACA were smaller than those located at other sites, whereas MCA a neu rysms we re large r tha n other an eury sms [4,14,15,26,33,34,36,39,44,47]. Multivariate analysis in this study demonstrated a significant association between the size of ruptured aneurysms and the presence of multiple aneurysms. Previous univariate analyses also showed that ruptured aneurysms in patients with multiple aneurysms were larger than those in patients with a single aneurysm [33,36]. In my recent study, history of hypertension was the most powerful risk factor for aneurysm formation but not related to the risk of aneurysm rupture [13]. Cigarette smoking increased the risk of both aneurysm formation and rupture [13]. Hypercholesterolemia, diabetes mellitus, and heart disease, which are associated with atherosclerosis, contributed to aneurysm formation, whereas they reduced the risk of aneurysm rupture [13]. However, risk factors influencing aneurysm size are not yet well understood. In the Cooperative Study of Intracranial Aneurysms, the ruptured aneurysms tended to be larger in hypertensive patients [30]. In contrast, Rosenørn and Eskesen [39] found no relationship between hypertension and the size of ruptured aneurysms. According to Qureshi et al [36], there was no apparent association between hypertension and aneurysm size, but cigarette smoking seemed to increase the risk for developing large aneurysms. Ohashi et al [33] reported that ruptured aneurysms were significantly smaller in patients with non- or poorly controlled hypertension than in normotensive patients but showed no difference between smokers and nonsmokers. In the present study, cigarette smoking was independently associated with large aneurysms, whereas hypertension, diabetes mellitus, nor alcohol consumption and hypercholesterolemia were related to aneurysm size. It is possible that cigarette smoking can increase the risk of SAH by aneurysm formation [13,24,35] and by increasing the growth rate of a preexisting aneurysm [23,24]. Qureshi et al [35-37] hypothesized that smoking promotes degradation of elastin in blood vessel walls, 90
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making them susceptible to dilatation because of the blood pressure load at anatomical sites of maximal turbulence. 4.2. Effects of aneurysm size on clinical features The present study showed that the larger the aneurysm, the worse was the WFNS grade on admission. This finding is in agreement with data from previous studies [36,38,39]. It is well-known that rebleeding of SAHs is especially common within 6 hours of onset [6,17]. However, in our previous hospital-based study, the rebleeding rate within 6 hours of initial SAH did not differ according to the size, shape, and site of ruptured aneurysms [17]. Kassell and Torner [26] reported that there was a relationship between aneurysm size and rebleeding before admission but not subsequent to admission. However, it remains unclear why there was a relationship between aneurysm size and rebleeding before admission but not subsequent to admission. In our previous autopsy study [16], the larger the aneurysms were, the higher the percentage of rebleeding: 11% in aneurysms of 4 mm or less in diameter, 32% in aneurysms of 5 to 9 mm in diameter, and 37% in aneurysms of 10 mm or more in diameter. In this study, the incidence of rebleeding was significantly higher in patients with larger (≥10 mm) aneurysms than in those with smaller (b10 mm) ones, and this also held true for the rate of rebleeding within 6 hours after SAH. Previous studies have demonstrated conflicting results regarding the effect of aneurysm size on the type or severity of SAH on CT scans. In an autopsy study [16], IVH was more frequent among patients with large (≥10 mm) aneurysms, whereas the frequency of ICH was not associated with aneurysm size. In contrast, in hospital-based clinical studies, the frequency of IVH was not associated with aneurysm size [36], whereas ICH was more frequent among patients with large aneurysms [36,39]. However, in the present study, the size of ruptured aneurysms was not related to the type of hemorrhage on CT scan. With respect to the severity of SAH on CT scans, most authors have emphasized that patients with smaller aneurysms tended to have more severe SAH than those with larger aneurysms [36,38,40,44]. Roos et al [38] reported that while patients with large (≥10 mm) aneurysms more often were in poor clinical condition on admission, they tended to have smaller amounts of SAH on admission CT, to have more episodes of rebleeding, and fewer episodes of ischemia. Qureshi et al [36] reported that the frequency of diffuse thick SAH was higher among patients with smaller (b13 mm) aneurysms, whereas a localized thick clot was more prevalent in patients with larger (≥13 mm) aneurysms. According to Russell et al [40], comparisons between 4 size groups (1-5, 6-10, 11-15, and N15 mm) showed that a smaller aneurysm size was correlated with a more extensive SAH. Taylor et al [44] showed that thick SAH was more common in patients with a very small (≤5 mm) aneurysm than in those with a larger (N5 mm) one, although there was no difference in the occurrence of vasospasm between them. However, none of those studies provided any appropriate explanation as
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to why smaller cerebral aneurysms produce more severe SAH. The observation that patients with smaller aneurysms tend to have more severe SAH than those with larger aneurysms appears to contradict that patients with larger aneurysms tend to be in poorer clinical condition than those with smaller aneurysms [36,38,39]. In addition, some problematic points related to comparison of the severity of SAH on CT scans were evident in those studies. For example, they did not exclude patients who had rebleeding before undergoing CT scan. It is more clear-cut to analyze the severity of SAH only in patients with SAH alone, excluding concomitant hematoma such as ICH or IVH. The timing of CT scans after SAH is also very important, as SAH on CT scans may diminish spontaneously even in the acute stage, and the diminution rate differs according to patient age, SAH grade, time from SAH to initial CT scan, and site of subarachnoid cisterns [18,19]. Only one previously reported study has been restricted to patients in whom CT scans were obtained within 24 hours after SAH [40]. In the present study, the incidences of diffuse severe SAH on CT scans and symptomatic vasospasm were higher in patients with larger (≥5 mm) aneurysms than in those with smaller (b5 mm) ones. In our previous studies, which used the same SAH grading system as that used in the present study, the SAH grades were well correlated with the incidence of vasospasm [5,20]. There is undoubtedly a strict correlation between the amount of cisternal blood detected by CT scan soon after SAH and the subsequent development of vasospasm. To date, the influence of the size of ruptured aneurysms on cerebral vasospasm has not been fully analyzed. Comparisons between the 3 aneurysm size groups (≤12 mm, 13-24 mm, and ≥25 mm) showed that aneurysm size was associated with the development of symptomatic vasospasm [31]. Hydrocephalus is a well-known sequela of aneurysmal SAH, and the pathogenesis of hydrocephalus is multifactorial. Many factors such as advanced age, female sex, hypertension, clinical grade, subarachnoid blood on CT scans, IVH, aneurysm site, rebleeding, and vasospasm have been associated with the occurrence of post-SAH hydrocephalus. However, previous studies dealing with hydrocephalus risk in relation to aneurysm size have been limited and have yielded conflicting results [42,44,46]. Sheehan et al [42] reported that aneurysm size was associated with hydrocephalus, whereas Taylor et al [44] and Vale et al [46] showed no statistically significant relationship between them. In the present study, 54% of the 195 patients who underwent surgery and who had preoperative grades I to IV underwent shunting procedures for treatment of hydrocephalus. This relatively higher than usual percentage may have been partly the result of a high proportion of elderly patients [9,12,48]. In this study, the incidence of hydrocephalus was higher in patients with larger (≥5 mm) aneurysms than in those with smaller (b5 mm) ones. In published studies, the issue of whether aneurysm size had a significant influence on outcome differed depending
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on the size level at which aneurysms were divided [27,36,38,39,44,47]. Outcome after SAH did not differ between patients with large (N5 mm) and small (≤5 mm) aneurysms [44]. In contrast, 2 studies showed that patients with larger (≥10 mm and ≥12 mm, respectively) aneurysms had a more unfavorable outcome than those with smaller (b10 mm and b12 mm, respectively) aneurysms after SAH [27,38]. The frequency of impaired functional outcome and mortality was higher in patients with large (11-24 mm) aneurysms than in those with small (≤10 mm) aneurysms [39]. Large (≥13 mm) aneurysms were associated with a higher rate of mortality at 3 months, independent of age and admission GCS score [36]. In the present study, the larger the aneurysm, the worse was either functional outcome or the 6-month and 2-year survival rates. The most important predictor of both 6-month and 2-year survival was clinical grade on admission, followed by incidence of rebleeding and the aneurysm site. However, aneurysm size per se did not influence the 6-month and 2-year case-fatality rates. In this series, patients with large aneurysms were often in poor clinical condition on admission and were less frequently treated by surgery. Therefore, the reason why aneurysm size was not a significant predictor of outcome is probably because there is a close correlation between this variable and clinical grade. 5. Conclusion The factors related to the size of ruptured aneurysms and the effects of aneurysm size on clinical features have been investigated in many previous studies. However, the results obtained in previous hospital-based studies have not been necessarily consistent. In Izumo, age (≥60 years of age) and cigarette smoking were independently associated with aneurysms 5 mm or more in diameter. Multiple aneurysms were positively and ACA aneurysms were inversely related to aneurysms of 10 mm or more in diameter. Compared with patients with smaller aneurysms, patients with larger aneurysms had a worse WFNS grade on admission, and SAH was more severe in patients with SAH alone on CT scans. These findings seem to be in good agreement with the higher incidences of rebleeding, symptomatic vasospasm, and hydrocephalus, and worse outcome, in patients with larger aneurysms. Further community-based studies are needed in this area. References [1] Carter BS, Sheth S, Chang E, Sethl M, Ogilvy CS. Epidemiology of the size distribution of intracranial bifurcation aneurysms: smaller size of distal aneurysms and increasing size of unruptured aneurysms with age. Neurosurgery 2006;58:217-23. [2] Cox DR. Regression models and life-tables. J R Stat Soc (B) 1972;34: 187-202. [3] Drake CG. Report of World Federation of Neurological Surgeons Committee on a Universal Subarachnoid Haemorrhage Grading Scale. J Neurosurg 1988;985-986:68 [letter].
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[4] Forget Jr TR, Benitez R, Veznedaroglu E, Sharan A, Mitchell W, Silva M, Rosenwasser RH. A review of size and location of ruptured intracranial aneurysms. Neurosurgery 2001;49:1322-6. [5] Inagawa T. Effect of early operation on cerebral vasospasm. Surg Neurol 1990;33:239-46. [6] Inagawa T. Ultra-early rebleeding within six hours after aneurysmal rupture. Surg Neurol 1994;42:130-4. [7] Inagawa T. What are the actual incidence and mortality rates of subarachnoid hemorrhage. Surg Neurol 1997;47:47-53. [8] Inagawa T. Dissection from fundus to neck for ruptured anterior and middle cerebral artery aneurysms at the acute stage. Acta Neurochir (Wien) 1999;141:563-70. [9] Inagawa T. Trends in incidence and case fatality rates of aneurysmal subarachnoid hemorrhage in Izumo City, Japan, between 1980-1989 and 1990-1998. Stroke 2001;32:1499-507. [10] Inagawa T. What are the actual incidence and mortality rates of intracerebral hemorrhage. Neurosurg Rev 2002;25:237-46. [11] Inagawa T. Risk factors for aneurysmal subarachnoid hemorrhage in patients in Izumo City, Japan. J Neurosurg 2005;102:60-7. [12] Inagawa T. Trends in surgical and management outcomes in patients with aneurysmal subarachnoid hemorrhage in Izumo City, Japan, between 1980-1989 and 1990-1998. Cerebrovasc Dis 2005;19:39-48. [13] Inagawa T. Risk factors for the formation and rupture of intracranial saccular aneurysms in Shimane, Japan. Surg Neurol 2009 [in press]. [14] Inagawa T, Hada H, Katoh Y. Unruptured intracranial aneurysms in elderly patients. Surg Neurol 1992;38:364-70. [15] Inagawa T, Hirano A. Autopsy study of unruptured incidental intracranial aneurysms. Surg Neurol 1990;34:361-5. [16] Inagawa T, Hirano A. Ruptured intracranial aneurysms: an autopsy study of 133 patients. Surg Neurol 1990;33:117-23. [17] Inagawa T, Kamiya K, Ogasawara H, Yano T. Rebleeding of ruptured intracranial aneurysms in the acute stage. Surg Neurol 1987;28:93-9. [18] Inagawa T, Ohbayashi N, Hada H. Rapid spontaneous diminution of cisternal blood on computed tomography in patients with subarachnoid hemorrhage. Surg Neurol 1995;44:356-64. [19] Inagawa T, Ohbayashi N, Kumano K. Effect of rapid spontaneous diminution of subarachnoid hemorrhage on cerebral vasospasm. Surg Neurol 1995;43:25-30. [20] Inagawa T, Yamamoto M, Kamiya K. Effect of clot removal on cerebral vasospasm. J Neurosurg 1990;72:224-30. [21] Inagawa T, Yamamoto M, Kamiya K, Ogasawara H. Management of elderly patients with aneurysmal subarachnoid hemorrhage. J Neurosurg 1988;69:332-9. [22] Jennett B, Bond M. Assessment of outcome after severe brain damage. A practical scale. Lancet 1975;1:480-4. [23] Juvela S, Porras M, Poussa K. Natural history of unruptured intracranial aneurysms: probability of and risk factors for aneurysm rupture. J Neurosurg 2000;93:379-87. [24] Juvela S, Poussa K, Porras M. Factors affecting formation and growth of intracranial aneurysms: a long-term follow-up study. Stroke 2001; 32:485-91. [25] Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-81. [26] Kassell NF, Torner JC. Size of intracranial aneurysms. Neurosurgery 1983;12:291-7. [27] Kassell NF, Torner JC, Haley Jr EC, Jane JA, Adams HP, Kongable GL. The International Cooperative Study on the Timing of Aneurysm Surgery. Part 1: overall management results. J Neurosurg 1990;73: 18-36. [28] Kongable GL, Lanzino G, Germanson TP, Truskowski LL, Alves WM, Torner JC, Kassell NF. Gender-related differences in aneurysmal subarachnoid hemorrhage. J Neurosurg 1996;84:43-8.
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[29] Lanzino G, Kassell NF, Germanson TP, Kongable GL, Truskowski LL, Torner JC, Jane JA, Participants T. Age and outcome after aneurysmal subarachnoid hemorrhage: why do older patients fare worse. J Neurosurg 1996;85:410-8. [30] Locksley HB. Report on the cooperative study of intracranial aneurysms and subarachnoid hemorrhage. Section V, Part II. Natural history of subarachnoid hemorrhage, intracranial aneurysms and arteriovenous malformations. Based on 6368 cases in the cooperative study. J Neurosurg 1966;25:321-68. [31] Macdonald RL, Rosengart A, Huo D, Karrison T. Factors associated with the development of vasospasm after planned surgical treatment of aneurysmal subarachnoid hemorrhage. J Neurosurg 2003;99: 644-52. [32] McCormick WF, Acosta-Rua GJ. The size of intracranial saccular aneurysms. An autopsy study. J Neurosurg 1970;33:422-7. [33] Ohashi Y, Horikoshi T, Sugita M, Yagishita T, Nukui H. Size of cerebral aneurysms and related factors in patients with subarachnoid hemorrhage. Surg Neurol 2004;61:239-47. [34] Orz Y, Kobayashi S, Osawa M, Tanaka Y. Aneurysm size: a prognostic factor for rupture. Br J Neurosurg 1997;11:144-9. [35] Qureshi AI, Suarez JI, Parekh PD, Sung G, Geocadin R, Bhardwaj A, Tamargo RJ, Ulatowski JA. Risk factors for multiple intracranial aneurysms. Neurosurgery 1998;43:22-7. [36] Qureshi AI, Sung GY, Suri MFK, Straw RN, Guterman LR, Hopkins LN. Factors associated with aneurysm size in patients with subarachnoid hemorrhage: effect of smoking and aneurysm location. Neurosurgery 2000;46:44-50. [37] Qureshi AI, Suri MF, Yahia AM, Suarez JI, Guterman LR, Hopkins LN, Tamargo RJ. Risk factors for subarachnoid hemorrhage. Neurosurgery 2001;49:607-13. [38] Roos EJ, Rinkel GJ, Velthuis BK, Algra A. The relation between aneurysm size and outcome in patients with subarachnoid hemorrhage. Neurology 2000;54:2334-6. [39] Rosenørn J, Eskesen V. Patients with ruptured intracranial saccular aneurysms: clinical features and outcome according to the size. Br J Neurosurg 1994;8:73-8. [40] Russell SM, Lin K, Hahn SA, Jafar JJ. Smaller cerebral aneurysms producing more extensive subarachnoid hemorrhage following rupture: a radiological investigation and discussion of theoretical determinants. J Neurosurg 2003;99:248-53. [41] Salary M, Quigley MR, Wilberger Jr JE. Relation among aneurysm size, amount of subarachnoid blood, and clinical outcome. J Neurosurg 2007;107:13-7. [42] Sheehan JP, Polin RS, Sheehan JM, Baskaya MK, Kassell NF. Factors associated with hydrocephalus after aneurysmal subarachnoid hemorrhage. Neurosurgery 1999;45:1120-8. [43] Sugai M, Shoji M. Pathogenesis of so-called congenital aneurysms of the brain. Acta Pathol Jpn 1968;18:139-60. [44] Taylor CL, Steele D, Kopitnik Jr TA, Samson DS, Purdy PD. Outcome after subarachnoid hemorrhage from a very small aneurysm: a casecontrol series. J Neurosurg 2004;100:623-5. [45] Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974;2:81-4. [46] Vale FL, Bradley EL, Fisher III WS. The relationship of subarachnoid hemorrhage and the need for postoperative shunting. J Neurosurg 1997;86:462-6. [47] Weir B, Disney L, Karrison T. Sizes of ruptured and unruptured aneurysms in relation to their sites and the ages of patients. J Neurosurg 2002;96:64-70. [48] Yoshioka H, Inagawa T, Tokuda Y, Inokuchi F. Chronic hydrocephalus in elderly patients following subarachnoid hemorrhage. Surg Neurol 2000;53:119-25.
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Size of ruptured intracranial saccular aneurysms in patients in Izumo City, Japan Tetsuji Inagawa MD, PhD⁎ Department of Neurosurgery, Shimane Prefectural Central Hospital, Izumo, Japan Received 2 May 2009; accepted 2 July 2009
Abstract
Background: A community-based study was conducted to evaluate the factors related to the size of ruptured aneurysms and the effects of aneurysm size on clinical features. Methods: Data from 358 patients with subarachnoid hemorrhage (SAH) treated between 1980 and 1998 in Izumo, Japan, were reviewed. In 285 of these patients, the sizes of the ruptured aneurysms were determined. Results: Aneurysm diameter was less than 5 mm in 68 patients, at least 5 to less than 10 mm in 137 patients, and 10 mm or more in 80 patients. Aneurysm size tended to increase with patient age. Age (≥60 years of age) and cigarette smoking were independently associated with aneurysms of 5 mm or more in diameter. Multiple aneurysms were positively and anterior cerebral artery aneurysms were inversely related to aneurysms of 10 mm or more in diameter. The larger the aneurysm, the worse was the World Federation of Neurosurgical Societies grade. The risk of rebleeding was higher in patients with larger (≥10 mm) aneurysms than in those with smaller (b10 mm) aneurysms. The incidences of diffuse severe SAH on computed tomographic scans in patients with SAH alone, symptomatic vasospasm, and hydrocephalus were higher in patients with larger (≥5 mm) aneurysms than in those with smaller (b5 mm) aneurysms. The larger the aneurysm, the worse was either functional outcome or the 6-month and 2-year survival rates. Conclusion: Age, cigarette smoking, multiple aneurysms, and aneurysm site appear to be related to the size of ruptured aneurysms. Patients with larger aneurysms seem to have a worse clinical condition and more severe SAH, resulting in higher incidences of rebleeding, symptomatic vasospasm and hydrocephalus, and a worse outcome. © 2010 Elsevier Inc. All rights reserved.
Keywords:
Aneurysm size; Cerebral aneurysm; Epidemiological study; Subarachnoid hemorrhage
1. Introduction Despite the recent advances in the management of ruptured intracranial aneurysm, the prognosis remains Abbreviations: ACA, anterior cerebral artery; CT, computed tomography; GCS, Glasgow Coma Scale; ICA, internal carotid artery; ICH, intracerebral hemorrhage; IVH, intraventricular hemorrhage; MCA, middle cerebral artery; SAH, subarachnoid hemorrhage; SDH, subdural hematoma; VBA, vertebrobasilar artery; WFNS, World Federation of Neurosurgical Societies. ⁎ Department of Neurosurgery, Araki Neurosurgical Hospital, Hiroshima, Hiroshima 733-0821, Japan. Tel.: +81 082 272 1114; fax: +81 082 272 7048. E-mail address: [email protected].
unsatisfactory. In Izumo City, Japan, the overall 6-month case fatality rate after aneurysmal SAH was 39%, and 13% of patients remained dependent on help [12]. The size of an intracranial aneurysm is an important prognostic factor for rupture; large aneurysms have a higher risk of rupture. After rupture, the size of the aneurysm lumen, that is, the angiographic aneurysm size, decreases due to formation of an intraaneurysm thrombus, which adheres to the inner wall at the point of rupture [8]. Various studies have investigated whether age [14,15,21,29,30,32,33,36,43,47] and some cerebrovascular risk factors [23,24,30,33,35-37,39], including hypertension and smoking, are related to the size of aneurysms, or whether aneurysm size affects the clinical
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features such as clinical condition [16,36,38-40,44], rebleeding [16,17,26], vasospasm [31,38,44], hydrocephalus [42,44,46], and outcome [27,36,38,39,41,44,47]. However, the results obtained have not necessarily been consistent, and some have been conflicting. These inconsistencies may be due in part to patient materials that have not been population based. The best data can be obtained from community-based studies that include all incident cases of disease, regardless of the age and clinical condition of the patient. Some population-based data on SAH are available, but no previous population-based studies have reported aneurysm features, including size and site. An ideal study would be a community-based one in which all diagnoses are systematically verified by neuroimaging. In the present study based in Izumo, I investigated risk factors related to the size of aneurysms that were confirmed by angiography, surgery and/or autopsy, and the effects of aneurysm size on clinical features.
2. Materials and methods Izumo City is located in the western part of Japan, covering a rural area of approximately 175 km2 and has 80 000 inhabitants. There is no heavy industry, and the social and demographic composition is relatively stable. Izumo has 4 hospitals, and CT scanning is an available procedure at each of them. Because 2 hospitals have both neurosurgical and neurologic departments and are designated emergency centers, all patients with verified or suspected SAH, even if moribund and regardless of age or condition, are immediately referred to the neurosurgical department of either hospital [9,11,12]. On admission, each patient's clinical condition was evaluated using the GCS [45]. To allow comparison of the patients in the present study with those in previously published studies, the clinical condition was classified according to the WFNS scale [3], which is based on the GCS score. Even if a patient was dead by the time of referral or was moribund on admission, we attempted to perform CT scanning studies whenever possible to confirm SAH, and clinical information was collected from relatives. In addition, I reviewed the death certificates and analyzed the records of those suspected of having died of hemorrhagic stroke [7,10]. Data were collected from the records of the 4 hospitals and the patients' death certificates [7-12]. Patients who died before hospital admission or who had a cardiorespiratory arrest on arrival were included in grade V. During the 19-year period between 1980 and 1998, aneurysmal SAH was diagnosed in 358 patients [9,12]. Five cases were picked up in the hospital charts after review of the death certificates. The other cases, however, were ascertained from the hospital charts without the need to review death certificates. The exact location of the ruptured aneurysm was confirmed in 291 (81%) of the 358 patients, excluding 1 patient with a dissecting aneurysm of the ACA. The size of the aneurysm was determined in 285 (98%) of the
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291 patients with saccular aneurysms—53 by angiography, 202 by angiography and surgery, 21 by angiography and autopsy, 6 by angiography, surgery and autopsy, 2 by autopsy, and 1 by CT angiography. Of the 6 aneurysms of which size was unknown, 2 were located on the ACA, 2 on the MCA, 1 on the ICA, and 1 on the basilar artery. The aneurysms were divided into 3 groups according to maximum diameter: less than 5 mm, at least 5 to less than 10 mm, and 10 mm or more. I collected data on the following risk factors: hypertension, diabetes mellitus, heart disease (valvular disease, coronary heart disease, and myocardial infarction), cigarette smoking, alcohol consumption, and serum total cholesterol level. Hypertension was defined as a history of the disorder, regardless of treatment with antihypertension medication. Information on diabetes and heart disease was based on medical history. Serum total cholesterol levels were obtained on admission to hospital. Details of the methods used for collecting the data and definitions of risk factors have been given elsewhere [11,13]. The diagnosis of rebleeding was described in our earlier studies in detail [6,17]. Episodes of rebleeding occurred in 81 (28%) of 285 patients: 21 patients before admission, 59 patients after admission, and 1 patient both before and after admission. Of these patients, 42 (52%) rebled within 6 hours. Aneurysmal SAH was classified by CT scan performed on admission into 4 anatomical types: SAH alone, ICH, IVH, and SDH [17]. In patients with SAH alone, SAH on the CT scan was graded from I to IV [5,20]. In this SAH grading, when SAH on CT scan was slight or moderate, it was classified as grade I or II, respectively. When a clot was severe and densely packed over a limited area, it was classified as grade III. If it was severe and densely packed over a diffuse area, it was classified as grade IV. After excluding 22 patients who had rebleeding before admission, the association between aneurysm size and the type of hemorrhage on the admission CT scan was evaluated in 263 patients. With respect to the association between aneurysm size and SAH grade in patients with SAH alone, analyses were restricted to the 155 patients who had no rebleeding before admission and were admitted within 24 hours after SAH. In the present study, clipping of ruptured aneurysms was defined as surgery; however, ventricular drainage alone and coil embolization for ruptured aneurysms were not. Symptomatic vasospasm was evaluated according to the criteria of Inagawa [5] and Inagawa et al [20]. Hydrocephalus was considered present if a ventriculoperitoneal shunt was placed during hospitalization. Symptomatic vasospasm and hydrocephalus were evaluated for 195 patients who underwent surgery and who had WFNS grades I to IV preoperatively because these features are difficult to assess if the patient's clinical condition is extremely poor. After discharge, the patients underwent a follow-up review by a variety of methods, including personal consultation, telephone interview, and written correspondence. Only 2
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Table 1 Baseline characteristics of 285 patients with ruptured cerebral aneurysms Category
P
Size of ruptured aneurysm (mm)
No. of patients Women Age (y) b60 ≥60 to b70 ≥70 Mean ± SD Site of ruptured aneurysm ACA ICA MCA VBA Multiple aneurysms Hypertension Present Absent Diabetes mellitus Present Absent Heart disease Present Absent Cigarette smoking Current regular & former smoker Nonsmoker Alcohol intake Daily drinking Occasional or no drinking Total cholesterol (mg/dL) ≥220 b220
b5
≥5 to b10
≥10
68 44 (65)
137 70 (51)
80 50 (63)
38 (56) 20 (29) 10 (15) 56.9 ± 12.6
60 (44) 33 (24) 44 (32) 62.5 ± 12.1
34 (43) 20 (25) 26 (33) 63.0 ± 13.1
.1020 .0386
Total cases
285 164 (58) 132 (46) 73 (26) 80 (28) 61.3 ± 12.7
.0101 38 10 16 4 18
(56) (15) (24) (6) (26)
64 (47) 30 (22) 35 (26) 8 (6) 29 (21)
21 (26) 29 (36) 24 (30) 6 (8) 30 (38)
34 (51) 33 (49)
67 (50) 67 (50)
39 (50) 39 (50)
3 (5) 61 (95)
3 (2) 126 (98)
2 (3) 63 (97)
2 (3) 62 (97)
14 (11) 116 (89)
4 (6) 61 (94)
16 (26) 45 (74)
60 (47) 69 (53)
26 (35) 49 (65)
17 (28) 44 (72)
48 (38) 80 (63)
16 (22) 58 (78)
16 (29) 40 (71)
25 (21) 92 (79)
17 (27) 45 (73)
.0326 .9943
123 (43) 69 (24) 75 (26) 18 (6) 77 (27) 140 (50) 139 (50)
.6721 8 (3) 250 (97) .1483 20 (8) 239 (92) .0198 102 (38) 163 (62) .0532 81 (31) 182 (69) .4973 58 (25) 177 (75)
VBA indicates vertebrobasilar artery. Values represent the number (%).
patients were lost to follow-up review in the 2 years after the initial SAH. The outcome at 6 months after SAH was classified according to the Glasgow Outcome Scale [22]. The χ2 test, Fisher exact test, or Spearman correlation coefficient by rank test was used for statistical analysis. I performed multiple logistic regression analysis to determine the variables associated with developing large aneurysms. For this analysis, the 3 categories of aneurysm size were combined to form 2 categories in 2 ways; one was division into less than 5 mm in diameter and 5 mm or more in diameter, and the other was division into less than 10 mm in diameter and 10 mm or more in diameter. The variables assessed were age, sex, site of ruptured aneurysms, single or multiple lesions, history of hypertension, diabetes mellitus,
heart disease, cigarette smoking, alcohol consumption, and total cholesterol on admission. The possibility of survival was estimated by the Kaplan-Meier product-limit method [25], and the curves for different groups were compared by the log-rank test. Multiple logistic regression analysis was performed to determine the variables associated with 6month case fatality, and the Cox proportional hazards analysis [2] was used to identify variables that predicted 2year survival. The variables assessed were age, sex, hours between onset and admission, WFNS grade on admission, site of ruptured aneurysms, rebleeding, any evidence of a concomitant hematoma on the CT scan, and maximum aneurysm diameter. Statistical analysis was performed using commercially available software (JMP Statistical Analysis
Table 2 Independent risk factors associated with large aneurysms, using multiple logistic regression analysis Size of ruptured aneurysm (mm) Variable
Categories
Odds ratio (95% confidence interval) P
≥5
≥60 or b60 y Current regular & former smoker or nonsmokers Multiple or single ACA aneurysm or other sites
3.3 (1.6-7.4) 5.5 (1.9-17.6) 2.0 (1.0-4.0) 0.4 (0.2-0.8)
≥10
86
Age Cigarette smoking Multiple aneurysms Site of ruptured aneurysms
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Table 3 Clinical characteristics and CT findings at admission in 285 patients with ruptured cerebral aneurysms Category
P
Size of ruptured aneurysm (mm)
No. of patients Admission within 6 h after SAH WFNS grade on admission I II or III IV V Rebleeding Type of hemorrhage on CT scan a SAH alone ICH IVH ICH + IVH SDH SAH grade in patients with SAH alone b I II III IV Surgery Preoperative WFNS grade I II or III IV V
b5
≥5 to b10
≥10
68 51 (75)
137 100 (73)
80 60 (75)
43 (63) 5 (7) 11 (16) 9 (13) 16 (24)
62 22 27 26 32
(45) (16) (20) (19) (23)
21 10 21 28 33
.9766 b.0001
(26) (13) (26) (35) (41)
51 (78) 6 (9) 1 (2) 7 (11) 0 (0)
101 (81) 11 (9) 6 (5) 4 (3) 2 (2)
53 (72) 5 (7) 8 (11) 7 (9) 1 (1)
9 (24) 11 (30) 12 (32) 5 (14) 55 (81)
18 (23) 16 (20) 21 (26) 25 (31) 106 (77)
7 10 11 10 47
(18) (26) (29) (26) (59)
16 13 11 7
(34) (28) (23) (15)
Total cases
.0111 .1505
285 211 (74) 126 (44) 37 (13) 59 (21) 63 (22) 81 (28) 205 (78) 22 (9) 15 (6) 18 (7) 3 (1)
.2676
34 (62) 11 (20) 8 (15) 2 (4)
52 22 28 4
(49) (21) (26) (4)
.0028 .0027
34 (22) 37 (24) 44 (28) 40 (26) 208 (73) 102 (49) 46 (22) 47 (23) 13 (6)
Values represent the number (%). a Analyses were performed on 263 patients who had no rebleeding before admission. b Analyses were performed on 155 patients who had no rebleeding before admission and were admitted within 24 hours after SAH. The percentages of SAH grades I to III and IV are 86% and 14% for patients with aneurysms less than 5 mm in diameter, respectively, and 70% and 30% for those with aneurysms of 5 mm or more, respectively (P = .0364).
Program [version 3.0], SAS Institute Inc, Cary, NC). Differences at P b .05 were considered to be significant. 3. Results 3.1. Factors related to aneurysm size The aneurysms were less than 5 mm in diameter in 68 patients (24%), at least 5 to less than 10 mm in 137 patients
(48%), and 10 mm or more in 80 patients (28%) (Table 1). Of 285 aneurysms, 13 (5%) were giant (≥25 mm) aneurysms. The ratio of women to men did not differ significantly among the 3 size groups. The size of ruptured aneurysms tended to increase with age. The frequency of ACA aneurysms was higher among smaller aneurysms, whereas ICA and MCA aneurysms were more common among larger aneurysms. The frequency of multiple aneurysms was higher in patients with aneurysms ≥10 mm in diameter (38%, 30 of 80 patients)
Table 4 Vasospasm and shunt-dependent hydrocephalus in 195 patients who underwent surgery and who had preoperative WFNS grades I to IV Category
No. of patients Vasospasm Permanent vasospasm Death from vasospasm Transient vasospasm Absent Shunt-dependent hydrocephalus Present Absent
P
Size of ruptured aneurysm (mm) b5
≥5 to b10
≥10
53
102
40
Total cases 195
.0815 4 (8) 1 4 (8) 45 (85)
17 (17) 3 15 (15) 70 (69)
7 (18) 1 5 (13) 28 (70)
21 (40) 32 (60)
66 (65) 36 (35)
19 (48) 21 (53)
28 (14) 5 24 (12) 143 (73) .0074 106 (54) 89 (46)
Values represent the number (%). The incidences of symptomatic (permanent and transient) vasospasm are 15% for patients with aneurysms of less than 5 mm in diameter and 31% for those with aneurysms of 5 mm or more (P = .0255), and the incidences of hydrocephalus are 40% and 60%, respectively (P = .0116).
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Table 5 Glasgow Outcome Scale scores at 6 months after onset in 285 patients with ruptured cerebral aneurysms Category
Surgical outcome Good recovery Moderate disability Severe disability Vegetative state Dead Management outcome Good recovery Moderate disability Severe disability Vegetative state Dead
Size of ruptured aneurysm (mm) b5
≥5 to b10
≥10
39 (71) 8 (15) 4 (7) 2 (4) 2 (4)
65 (61) 12 (11) 18 (17) 5 (5) 6 (6)
27 4 5 5 6
(57) (9) (11) (11) (13)
39 (57) 8 (12) 4 (6) 3 (4) 14 (21)
65 (47) 13 (9) 18 (13) 6 (4) 35 (26)
29 4 7 5 35
(36) (5) (9) (6) (44)
P
Total cases
.0534 131 (63) 24 (12) 27 (13) 12 (6) 14 (7) .0010 133 (47) 25 (9) 29 (10) 14 (5) 84 (29)
Values represent the number (%).
compared with those with aneurysms of less than 10 mm (23%; 47/205 patients) (P = .0127). Aneurysm size was associated with cigarette smoking but not with other risk factors. The proportion of smokers was 26% (16/61 patients) among patients with aneurysms of less than 5 mm in diameter and 42% (86/204 patients) among those with aneurysms of 5 mm or more (P = .0248). Age (≥60 years of age) and cigarette smoking were independently associated with aneurysms of 5 mm or more in diameter, and multiple aneurysms were positively related to those 10 mm or more in diameter (Table 2). In contrast, ACA aneurysms were inversely associated aneurysms of 10 mm or more in diameter. 3.2. Effects of aneurysm size on clinical features Of the 285 patients with ruptured aneurysms, 211 (74%) were admitted within 6 hours after onset (Table 3). The larger
the aneurysm, the worse was the WFNS grade on admission. The risk of rebleeding was approximately 2-fold in patents with aneurysms of 10 mm or more in diameter compared with those with aneurysms of less than 10 mm (P = .0027). The rebleeding rate within 6 hours after initial SAH was also significantly higher in patients with aneurysms of 10 mm or more in diameter (23%, 18/80 patients) than in those with aneurysms of less than 10 mm (12%, 24/205 patients) (P = .0209). There was no significant difference in the type of hemorrhage on CT scan among the 3 size groups. With respect to the association between aneurysm size and SAH grade in patients with SAH alone, there was also no significant difference among the 3 size groups. However, the percentage of SAH grade IV was significantly higher in patients with aneurysms of 5 mm or more in diameter (30%, 35/118 patients) compared with those with aneurysms of less than 5 mm (14%, 5/37 patients) (P = .0364). Surgery was performed on 208 (73%) patients. Patients with larger aneurysms tended to be operated on less frequently, and the larger the aneurysm, the worse was the preoperative grade. The main reason for withholding surgery was poor patient condition because of the direct effect of the aneurysm rupture itself, followed by rebleeding. The percentages of patients who were not operated on because of their poor condition were 9% (6/68 patients) among those with aneurysms of less than 5 mm in diameter, 13% (18/137 patients) among those with aneurysms of at least 5 to less than 10 mm in diameter, and 21% (17/80 patients) among those with aneurysms of 10 mm or more in diameter. Of the 77 patients who did not undergo surgery, 7 were treated with coil embolization for ruptured aneurysms: these included 2 aneurysms of less than 5 mm in diameter, 2 aneurysms of at least 5 to less than 10 mm in diameter, and 3 aneurysms of 10 mm or more in diameter. The main reasons for endovascular therapy included the advanced age of the patient and/or poor clinical status at admission: 1 patient in grade IV and 6 in grade V.
Fig. 1. Graphs showing comparisons of 2-year survival curves for patients with ruptured aneurysms in relation to aneurysm size. Left, Operative patients. Right, Management patients.
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Table 6 Survival P values in multivariate analysis Variable
Sex Age (y) Hours between onset and admission WFNS grade on admission Rebleeding Site of ruptured aneurysms Concomitant hematoma on CT scan c Size of ruptured aneurysms (mm) a b c
Categories
Female or male b60 or ≥60 Within or after 6 h I-III or IV-V Presence or absence ACA, ICA, MCA, or VBA Presence or absence b5, ≥5 to b10, or ≥10
6-month survival a
2-y survival b
Size of ruptured aneurysm (mm)
Size of ruptured aneurysm (mm)
b5
≥5 to b10 ≥10
0.1149 0.1067 0.1538 0.0347 0.1386 0.9631 0.9828
0.5932 0.2306 0.4465 0.0004 0.9620 0.4665 0.8310
Total cases b5
0.1235 0.1406 0.5710 0.1553 0.0398 0.0354 0.0022 b0.0001 0.0019 0.0004 0.0727 0.0020 0.1970 0.3600 0.4533
0.0008 0.0120 0.5427 0.0057 0.0012 0.4281 0.5430
≥5 to b10 ≥10 0.4662 0.1130 0.6925 0.0003 0.4998 0.5001 0.5917
Total cases
0.2153 0.0168 0.3676 0.0169 0.1486 0.1712 0.0011 b0.0001 0.0050 b0.0001 0.2502 0.0083 0.3942 0.7870 0.1556
Statistical analyses were performed using the multiple logistic regression analysis. Statistical analyses were performed using the Cox proportional hazards model. Intracerebral hemorrhage, massive IVH, or SDH.
The number of patients who underwent surgery and who had preoperative WFNS grades I to IV was 195 (Table 4). Of these patients, 52 (27%) had symptomatic vasospasm, including permanent and transient vasospasms, and 106 (54%) developed shunt-dependent hydrocephalus. When dividing patients into those with aneurysms of less than 5 mm in diameter and those with aneurysms of 5 mm or more in diameter, symptomatic vasospasm was observed in 15% (8/53 patients) and 31% (44/142 patients), respectively (P = .0255), and hydrocephalus occurred in 40% (21/53 patients) and 60% (85/142 patients), respectively (P = .0116). The larger the aneurysm, the worse both surgical and management outcomes became (Table 5). However, in patients who underwent surgery, the differences among the 3 size groups did not reach statistical significance. Furthermore, when stratified by WFNS grade, there were no evident significant differences in surgical or management outcome among the 3 groups. The 6-month case fatality rates after SAH were 7% for patients who underwent surgery and 29% for patients overall, managed by a variety of methods. The leading cause of death was the direct effect of aneurysm rupture itself. The percentages of patients who died of such a direct effect were 7% (5/68 patients) among those with aneurysms of less than 5 mm in diameter, 14% (19/137 patients) among those with aneurysms of at least 5 to less than 10 mm in diameter, and 26% (21/80 patients) among those with aneurysms of 10 mm or more in diameter. When comparing the 2-year survival curves among the 3 size groups, there were significant differences both in patients who were treated surgically and in patients overall who were managed using a variety of methods (Fig. 1). The larger the aneurysm, the worse the survival curves became. The differences were less significant in patients who were treated surgically than in those who were managed overall. In patients who were treated surgically, the cumulative 2-year survival rates were 93% for those with aneurysms of less than 5 mm in diameter, 89% for those with aneurysms of at least 5 to less than 10 mm in diameter, 74% for those with aneurysms of 10 mm or more in diameter, and 87% as a
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whole, whereas in patients who were managed overall, these rates were 76%, 70%, 48%, and 65%, respectively. When all patients were included, the most important predictors of both the 6-month and 2-year survival rates, in order of decreasing reliability, were WFNS grade on admission, rebleeding, and the site of the ruptured aneurysm (Table 6). Sex and age were also significant predictors of the 2-year survival rate, but they were not significant predictors of the 6-month case fatality rate. In patients with aneurysms of less than 5 mm in diameter, only WFNS grade on admission was a significant predictor of 6-month survival, whereas significant predictors of 2-year survival, in order of decreasing reliability, were sex, rebleeding, WFNS grade on admission, and age. In patients with aneurysms of at least 5 to less than 10 mm in diameter, only WFNS grade on admission was a significant predictor of both the 6-month and 2-year survival rates. In patients with aneurysms of 10 mm or more in diameter, WFNS grade on admission and rebleeding were significant predictors of both the 6-month and 2-year survival rates, and the length of time between onset and admission was also a significant predictor of 6-month survival.
4. Discussion 4.1. Factors related to aneurysm size In published studies, it has been controversial whether the size of ruptured aneurysms differs with patient age. Most hospital-based studies have shown that the size of ruptured aneurysms did not increase with age [1,14,21,29,33,36,47]. In contrast, according to the Cooperative Study of Intracranial Aneurysms [30], the size of ruptured aneurysms tended to increase with age. In autopsy studies, Sugai and Shoji [43] suggested that large aneurysms were more common in the elderly, whereas Inagawa and Hirano [15] and McCormick and Acosta-Rua [32] found no relationship between patient age and aneurysm size. In the present study, aneurysms tended to be larger in the older age groups. When
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considering that the incidence of aneurysmal SAH increases with increasing age [7,9] and atherosclerosis of the circle of Willis is more prominent in older patients [16], aneurysms in the elderly may not rupture as easily as those in younger patients. This may be one of the reasons why there was a relationship between aneurysm size and age. A limitation of this study was that the exact size of the ruptured aneurysm was not determined in 73 (20%) of the 358 patients with aneurysmal SAH, mainly because of their poor clinical condition and/or very old age. When taking into account the rapid increase in the number of very elderly people in most countries, it is vitally important to obtain reliable information about elderly patients. The size of the ruptured aneurysm did not differ significantly between women and men, similar to findings reported previously [28,33,36,39]. In the present study, ruptured ACA aneurysms were smaller than ICA or MCA aneurysms. Earlier studies also found that ruptured aneurysms located in the ACA were smaller than those located at other sites, whereas MCA a neu rysms we re large r tha n other an eury sms [4,14,15,26,33,34,36,39,44,47]. Multivariate analysis in this study demonstrated a significant association between the size of ruptured aneurysms and the presence of multiple aneurysms. Previous univariate analyses also showed that ruptured aneurysms in patients with multiple aneurysms were larger than those in patients with a single aneurysm [33,36]. In my recent study, history of hypertension was the most powerful risk factor for aneurysm formation but not related to the risk of aneurysm rupture [13]. Cigarette smoking increased the risk of both aneurysm formation and rupture [13]. Hypercholesterolemia, diabetes mellitus, and heart disease, which are associated with atherosclerosis, contributed to aneurysm formation, whereas they reduced the risk of aneurysm rupture [13]. However, risk factors influencing aneurysm size are not yet well understood. In the Cooperative Study of Intracranial Aneurysms, the ruptured aneurysms tended to be larger in hypertensive patients [30]. In contrast, Rosenørn and Eskesen [39] found no relationship between hypertension and the size of ruptured aneurysms. According to Qureshi et al [36], there was no apparent association between hypertension and aneurysm size, but cigarette smoking seemed to increase the risk for developing large aneurysms. Ohashi et al [33] reported that ruptured aneurysms were significantly smaller in patients with non- or poorly controlled hypertension than in normotensive patients but showed no difference between smokers and nonsmokers. In the present study, cigarette smoking was independently associated with large aneurysms, whereas hypertension, diabetes mellitus, nor alcohol consumption and hypercholesterolemia were related to aneurysm size. It is possible that cigarette smoking can increase the risk of SAH by aneurysm formation [13,24,35] and by increasing the growth rate of a preexisting aneurysm [23,24]. Qureshi et al [35-37] hypothesized that smoking promotes degradation of elastin in blood vessel walls, 90
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making them susceptible to dilatation because of the blood pressure load at anatomical sites of maximal turbulence. 4.2. Effects of aneurysm size on clinical features The present study showed that the larger the aneurysm, the worse was the WFNS grade on admission. This finding is in agreement with data from previous studies [36,38,39]. It is well-known that rebleeding of SAHs is especially common within 6 hours of onset [6,17]. However, in our previous hospital-based study, the rebleeding rate within 6 hours of initial SAH did not differ according to the size, shape, and site of ruptured aneurysms [17]. Kassell and Torner [26] reported that there was a relationship between aneurysm size and rebleeding before admission but not subsequent to admission. However, it remains unclear why there was a relationship between aneurysm size and rebleeding before admission but not subsequent to admission. In our previous autopsy study [16], the larger the aneurysms were, the higher the percentage of rebleeding: 11% in aneurysms of 4 mm or less in diameter, 32% in aneurysms of 5 to 9 mm in diameter, and 37% in aneurysms of 10 mm or more in diameter. In this study, the incidence of rebleeding was significantly higher in patients with larger (≥10 mm) aneurysms than in those with smaller (b10 mm) ones, and this also held true for the rate of rebleeding within 6 hours after SAH. Previous studies have demonstrated conflicting results regarding the effect of aneurysm size on the type or severity of SAH on CT scans. In an autopsy study [16], IVH was more frequent among patients with large (≥10 mm) aneurysms, whereas the frequency of ICH was not associated with aneurysm size. In contrast, in hospital-based clinical studies, the frequency of IVH was not associated with aneurysm size [36], whereas ICH was more frequent among patients with large aneurysms [36,39]. However, in the present study, the size of ruptured aneurysms was not related to the type of hemorrhage on CT scan. With respect to the severity of SAH on CT scans, most authors have emphasized that patients with smaller aneurysms tended to have more severe SAH than those with larger aneurysms [36,38,40,44]. Roos et al [38] reported that while patients with large (≥10 mm) aneurysms more often were in poor clinical condition on admission, they tended to have smaller amounts of SAH on admission CT, to have more episodes of rebleeding, and fewer episodes of ischemia. Qureshi et al [36] reported that the frequency of diffuse thick SAH was higher among patients with smaller (b13 mm) aneurysms, whereas a localized thick clot was more prevalent in patients with larger (≥13 mm) aneurysms. According to Russell et al [40], comparisons between 4 size groups (1-5, 6-10, 11-15, and N15 mm) showed that a smaller aneurysm size was correlated with a more extensive SAH. Taylor et al [44] showed that thick SAH was more common in patients with a very small (≤5 mm) aneurysm than in those with a larger (N5 mm) one, although there was no difference in the occurrence of vasospasm between them. However, none of those studies provided any appropriate explanation as
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to why smaller cerebral aneurysms produce more severe SAH. The observation that patients with smaller aneurysms tend to have more severe SAH than those with larger aneurysms appears to contradict that patients with larger aneurysms tend to be in poorer clinical condition than those with smaller aneurysms [36,38,39]. In addition, some problematic points related to comparison of the severity of SAH on CT scans were evident in those studies. For example, they did not exclude patients who had rebleeding before undergoing CT scan. It is more clear-cut to analyze the severity of SAH only in patients with SAH alone, excluding concomitant hematoma such as ICH or IVH. The timing of CT scans after SAH is also very important, as SAH on CT scans may diminish spontaneously even in the acute stage, and the diminution rate differs according to patient age, SAH grade, time from SAH to initial CT scan, and site of subarachnoid cisterns [18,19]. Only one previously reported study has been restricted to patients in whom CT scans were obtained within 24 hours after SAH [40]. In the present study, the incidences of diffuse severe SAH on CT scans and symptomatic vasospasm were higher in patients with larger (≥5 mm) aneurysms than in those with smaller (b5 mm) ones. In our previous studies, which used the same SAH grading system as that used in the present study, the SAH grades were well correlated with the incidence of vasospasm [5,20]. There is undoubtedly a strict correlation between the amount of cisternal blood detected by CT scan soon after SAH and the subsequent development of vasospasm. To date, the influence of the size of ruptured aneurysms on cerebral vasospasm has not been fully analyzed. Comparisons between the 3 aneurysm size groups (≤12 mm, 13-24 mm, and ≥25 mm) showed that aneurysm size was associated with the development of symptomatic vasospasm [31]. Hydrocephalus is a well-known sequela of aneurysmal SAH, and the pathogenesis of hydrocephalus is multifactorial. Many factors such as advanced age, female sex, hypertension, clinical grade, subarachnoid blood on CT scans, IVH, aneurysm site, rebleeding, and vasospasm have been associated with the occurrence of post-SAH hydrocephalus. However, previous studies dealing with hydrocephalus risk in relation to aneurysm size have been limited and have yielded conflicting results [42,44,46]. Sheehan et al [42] reported that aneurysm size was associated with hydrocephalus, whereas Taylor et al [44] and Vale et al [46] showed no statistically significant relationship between them. In the present study, 54% of the 195 patients who underwent surgery and who had preoperative grades I to IV underwent shunting procedures for treatment of hydrocephalus. This relatively higher than usual percentage may have been partly the result of a high proportion of elderly patients [9,12,48]. In this study, the incidence of hydrocephalus was higher in patients with larger (≥5 mm) aneurysms than in those with smaller (b5 mm) ones. In published studies, the issue of whether aneurysm size had a significant influence on outcome differed depending
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on the size level at which aneurysms were divided [27,36,38,39,44,47]. Outcome after SAH did not differ between patients with large (N5 mm) and small (≤5 mm) aneurysms [44]. In contrast, 2 studies showed that patients with larger (≥10 mm and ≥12 mm, respectively) aneurysms had a more unfavorable outcome than those with smaller (b10 mm and b12 mm, respectively) aneurysms after SAH [27,38]. The frequency of impaired functional outcome and mortality was higher in patients with large (11-24 mm) aneurysms than in those with small (≤10 mm) aneurysms [39]. Large (≥13 mm) aneurysms were associated with a higher rate of mortality at 3 months, independent of age and admission GCS score [36]. In the present study, the larger the aneurysm, the worse was either functional outcome or the 6-month and 2-year survival rates. The most important predictor of both 6-month and 2-year survival was clinical grade on admission, followed by incidence of rebleeding and the aneurysm site. However, aneurysm size per se did not influence the 6-month and 2-year case-fatality rates. In this series, patients with large aneurysms were often in poor clinical condition on admission and were less frequently treated by surgery. Therefore, the reason why aneurysm size was not a significant predictor of outcome is probably because there is a close correlation between this variable and clinical grade. 5. Conclusion The factors related to the size of ruptured aneurysms and the effects of aneurysm size on clinical features have been investigated in many previous studies. However, the results obtained in previous hospital-based studies have not been necessarily consistent. In Izumo, age (≥60 years of age) and cigarette smoking were independently associated with aneurysms 5 mm or more in diameter. Multiple aneurysms were positively and ACA aneurysms were inversely related to aneurysms of 10 mm or more in diameter. Compared with patients with smaller aneurysms, patients with larger aneurysms had a worse WFNS grade on admission, and SAH was more severe in patients with SAH alone on CT scans. These findings seem to be in good agreement with the higher incidences of rebleeding, symptomatic vasospasm, and hydrocephalus, and worse outcome, in patients with larger aneurysms. Further community-based studies are needed in this area. References [1] Carter BS, Sheth S, Chang E, Sethl M, Ogilvy CS. Epidemiology of the size distribution of intracranial bifurcation aneurysms: smaller size of distal aneurysms and increasing size of unruptured aneurysms with age. Neurosurgery 2006;58:217-23. [2] Cox DR. Regression models and life-tables. J R Stat Soc (B) 1972;34: 187-202. [3] Drake CG. Report of World Federation of Neurological Surgeons Committee on a Universal Subarachnoid Haemorrhage Grading Scale. J Neurosurg 1988;985-986:68 [letter].
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[4] Forget Jr TR, Benitez R, Veznedaroglu E, Sharan A, Mitchell W, Silva M, Rosenwasser RH. A review of size and location of ruptured intracranial aneurysms. Neurosurgery 2001;49:1322-6. [5] Inagawa T. Effect of early operation on cerebral vasospasm. Surg Neurol 1990;33:239-46. [6] Inagawa T. Ultra-early rebleeding within six hours after aneurysmal rupture. Surg Neurol 1994;42:130-4. [7] Inagawa T. What are the actual incidence and mortality rates of subarachnoid hemorrhage. Surg Neurol 1997;47:47-53. [8] Inagawa T. Dissection from fundus to neck for ruptured anterior and middle cerebral artery aneurysms at the acute stage. Acta Neurochir (Wien) 1999;141:563-70. [9] Inagawa T. Trends in incidence and case fatality rates of aneurysmal subarachnoid hemorrhage in Izumo City, Japan, between 1980-1989 and 1990-1998. Stroke 2001;32:1499-507. [10] Inagawa T. What are the actual incidence and mortality rates of intracerebral hemorrhage. Neurosurg Rev 2002;25:237-46. [11] Inagawa T. Risk factors for aneurysmal subarachnoid hemorrhage in patients in Izumo City, Japan. J Neurosurg 2005;102:60-7. [12] Inagawa T. Trends in surgical and management outcomes in patients with aneurysmal subarachnoid hemorrhage in Izumo City, Japan, between 1980-1989 and 1990-1998. Cerebrovasc Dis 2005;19:39-48. [13] Inagawa T. Risk factors for the formation and rupture of intracranial saccular aneurysms in Shimane, Japan. Surg Neurol 2009 [in press]. [14] Inagawa T, Hada H, Katoh Y. Unruptured intracranial aneurysms in elderly patients. Surg Neurol 1992;38:364-70. [15] Inagawa T, Hirano A. Autopsy study of unruptured incidental intracranial aneurysms. Surg Neurol 1990;34:361-5. [16] Inagawa T, Hirano A. Ruptured intracranial aneurysms: an autopsy study of 133 patients. Surg Neurol 1990;33:117-23. [17] Inagawa T, Kamiya K, Ogasawara H, Yano T. Rebleeding of ruptured intracranial aneurysms in the acute stage. Surg Neurol 1987;28:93-9. [18] Inagawa T, Ohbayashi N, Hada H. Rapid spontaneous diminution of cisternal blood on computed tomography in patients with subarachnoid hemorrhage. Surg Neurol 1995;44:356-64. [19] Inagawa T, Ohbayashi N, Kumano K. Effect of rapid spontaneous diminution of subarachnoid hemorrhage on cerebral vasospasm. Surg Neurol 1995;43:25-30. [20] Inagawa T, Yamamoto M, Kamiya K. Effect of clot removal on cerebral vasospasm. J Neurosurg 1990;72:224-30. [21] Inagawa T, Yamamoto M, Kamiya K, Ogasawara H. Management of elderly patients with aneurysmal subarachnoid hemorrhage. J Neurosurg 1988;69:332-9. [22] Jennett B, Bond M. Assessment of outcome after severe brain damage. A practical scale. Lancet 1975;1:480-4. [23] Juvela S, Porras M, Poussa K. Natural history of unruptured intracranial aneurysms: probability of and risk factors for aneurysm rupture. J Neurosurg 2000;93:379-87. [24] Juvela S, Poussa K, Porras M. Factors affecting formation and growth of intracranial aneurysms: a long-term follow-up study. Stroke 2001; 32:485-91. [25] Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-81. [26] Kassell NF, Torner JC. Size of intracranial aneurysms. Neurosurgery 1983;12:291-7. [27] Kassell NF, Torner JC, Haley Jr EC, Jane JA, Adams HP, Kongable GL. The International Cooperative Study on the Timing of Aneurysm Surgery. Part 1: overall management results. J Neurosurg 1990;73: 18-36. [28] Kongable GL, Lanzino G, Germanson TP, Truskowski LL, Alves WM, Torner JC, Kassell NF. Gender-related differences in aneurysmal subarachnoid hemorrhage. J Neurosurg 1996;84:43-8.
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SIZE OF RUPTURED INTRACRANIAL SACCULAR ANEURYSMS
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DOI:10.1016/J.SURNEU.2009.07.001