Female sex as a risk factor for the growth of asymptomatic unruptured cerebral saccular aneurysms in elderly patients

Clinical article

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Object

The prevalence of patients with asymptomatic unruptured intracranial aneurysms (UIAs) increases with the advancing age of the general population. The goal of the present study was to identify risk factors for the growth of UIAs detected with serial MR angiography (MRA) in patients 70 years of age or older.

Methods

This prospective study enrolled 79 patients (age range 70–84 years) with 98 UIAs. Patients were followed up every 4 months, including an assessment of the aneurysm diameter and morphological changes on MRA, neurological status, and other medical conditions. Aneurysm growth was categorized into two different patterns on the basis of the MRA findings: 1) maximum increase in aneurysm diameter of 2 mm or more; and 2) obvious morphological change, such as the appearance of a bleb.

Results

The mean duration of follow-up was 38.5 months (250.2 patient-years). Aneurysm rupture did not occur, but aneurysm growth was observed in 8 aneurysms (8 patients) during the study period. Univariate analysis showed that female sex, patient age ≥ 75 years, and an aneurysm location in the internal carotid artery (ICA) or middle cerebral artery (MCA) were associated with aneurysm growth (p = 0.04, p = 0.04, and p < 0.001, respectively). Multivariate analysis demonstrated that female sex was the only independent predictor of aneurysm growth (p = 0.0313, OR 2.3, 95% CI 1.3–30.2).

Conclusions

Female sex is an independent risk factor for the growth of UIAs in elderly patients. In addition, an age ≥ 75 years and aneurysm location in the ICA or MCA are characteristics that may warrant additional attention during follow-up imaging.

Abbreviations used in this paper:ACA = anterior cerebral artery; ACoA = anterior communicating artery; CTA = CT angiography; HICH = hypertensive intracerebral hemorrhage; ICA = internal carotid artery; MCA = middle cerebral artery; MRA = MR angiography; PCoA = posterior communicating artery; SAH = subarachnoid hemorrhage; UIA = unruptured intracranial saccular aneurysm.

Object

The prevalence of patients with asymptomatic unruptured intracranial aneurysms (UIAs) increases with the advancing age of the general population. The goal of the present study was to identify risk factors for the growth of UIAs detected with serial MR angiography (MRA) in patients 70 years of age or older.

Methods

This prospective study enrolled 79 patients (age range 70–84 years) with 98 UIAs. Patients were followed up every 4 months, including an assessment of the aneurysm diameter and morphological changes on MRA, neurological status, and other medical conditions. Aneurysm growth was categorized into two different patterns on the basis of the MRA findings: 1) maximum increase in aneurysm diameter of 2 mm or more; and 2) obvious morphological change, such as the appearance of a bleb.

Results

The mean duration of follow-up was 38.5 months (250.2 patient-years). Aneurysm rupture did not occur, but aneurysm growth was observed in 8 aneurysms (8 patients) during the study period. Univariate analysis showed that female sex, patient age ≥ 75 years, and an aneurysm location in the internal carotid artery (ICA) or middle cerebral artery (MCA) were associated with aneurysm growth (p = 0.04, p = 0.04, and p < 0.001, respectively). Multivariate analysis demonstrated that female sex was the only independent predictor of aneurysm growth (p = 0.0313, OR 2.3, 95% CI 1.3–30.2).

Conclusions

Female sex is an independent risk factor for the growth of UIAs in elderly patients. In addition, an age ≥ 75 years and aneurysm location in the ICA or MCA are characteristics that may warrant additional attention during follow-up imaging.

While many previous studies have described risk factors for the rupture10,17,19,20,25,28,30,31 and growth2–4,6,9,13,16,18,25 of asymptomatic unruptured intracranial saccular aneurysms (UIAs) in the general population, few have evaluated risk factors for aneurysm growth in the elderly population.16 Therefore, indications for the surgical repair of UIAs in elderly patients remain controversial. Given that autopsies show that the incidence of UIAs increases with advancing age,11 the prevalence of patients with asymptomatic UIAs is expected to increase as the general population ages.5 As patient age increases, a number of factors must be considered when determining whether to pursue treatment, including the estimated risk that an individual aneurysm will rupture, the medical and neurological condition of the patient, the estimated surgical and/or endovascular treatment risks given the aneurysm's size, the location and anatomical configuration of the aneurysm, the patient's life expectancy, the patient and family expectations of acceptable outcomes, and the phenomenon of individual discounting. More information regarding these issues can assist the practicing neurosurgeon in counseling elderly patients and their families on whether to treat an aneurysm. Aneurysm growth is probably associated with rupture, but this relationship has not been well characterized. Therefore, elderly patients with aneurysm growth must be identified and followed via noninvasive methods, such as MR angiography (MRA). The goal in the present study was to identify risk factors for the growth of UIAs detected by serial MRA in patients 70 years of age or older.

Methods

Patient Population

All protocols were reviewed and approved by the local institutional ethics committee. In this prospective study we enrolled 79 patients (age range 70–84 years) with 98 UIAs between April 2006 and March 2013. Inclusion criteria were a UIA ≥ 2 mm in diameter confirmed on MRA and/or 3D CT angiography (CTA) and the provision of informed consent. Exclusion criteria were symptoms from compression by the UIA; severe medical conditions, such as malignant neoplasm, cardiac failure, or renal failure requiring hemodialysis; and refusal to provide informed consent.

Of 163 UIAs (134 patients) examined in the study period, 65 aneurysms (55 patients) were excluded. Reasons for exclusion included compression of a cranial nerve or brain by the aneurysm (6 aneurysms, 6 patients); clipping surgery (20 aneurysms, 18 patients); aneurysms < 2 mm in size (27 aneurysms, 22 patients); severe medical conditions, such as malignant neoplasm, cardiac failure, or renal failure requiring hemodialysis (10 aneurysms, 7 patients); and refusal to participate in the study (2 aneurysms, 2 patients). Thus, this study included 98 aneurysms in 79 patients, including 21 men and 58 women, ranging in age from 70 to 84 years (mean age 73.9 ± 3.3 years).

Data gathered at the beginning of follow-up included patient sex, age, multiplicity of aneurysms, history of concomitant diseases (for example, hypertension, hyperlipidemia, diabetes mellitus, ischemic heart disease, cerebral infarction, hypertensive intracerebral hemorrhage [HICH], aneurysmal subarachnoid hemorrhage [SAH], current smoking status, family history of UIAs, and characteristics of UIAs [location, diameter]). Hypertension was defined as repeated episodes of systolic blood pressure ≥ 140 mm Hg or as diastolic pressure ≥ 90 mm Hg during visits to a family physician and/or the use of antihypertensive medication. Diabetes mellitus was diagnosed based on the presence of any one of the following: 1) fasting plasma glucose ≥ 126 mg/dl; 2) plasma glucose ≥ 200 mg/dl at 2 hours after a 75-g oral glucose load (that is, glucose tolerance test); 3) casual plasma glucose ≥ 200 mg/dl; or 4) hemoglobin A1c (HbA1c) ≥ 6.5%. Hyperlipidemia was defined as total cholesterol ≥ 240 mg/dl, lowdensity lipoprotein cholesterol ≥ 160 mg/dl, high-density lipoprotein cholesterol ≤ 35 mg/dl, or triglycerides ≥ 200 mg/dl. A family history of intracranial aneurysm was defined as any verified aneurysms in first-degree relatives. A contributor (Y.K.) to this study interviewed all patients while filling out a structured checklist. Two neurosurgeons (Y.K. and T.K.) measured aneurysm size on sagittal and axial MRA images. We categorized aneurysm growth into two different patterns on the basis of the MRA findings: 1) maximum aneurysm diameter increase by 2 mm or more; and 2) obvious morphological change, such as the appearance of a bleb. Three-dimensional CTA was used to confirm the exact size of aneurysms, but it was not used for follow-up examination. Three-dimensional CTA was performed after the injection of nonionic contrast material at a continuous flow of 2 ml/second and a total of 80–100 ml so that ≥ 250 intravascular HU could be obtained. Catheter-directed angiography was not performed for routine follow-up. If aneurysm growth was considered to have occurred during the course of observation, the subsequent treatment strategy was based on the policy at our institute. Indications for surgery for a UIA were based on the following Japanese Guidelines for the Management of Stroke 2004:24 1) life expectancy > 15 years, 2) aneurysm size > 5 mm, or 3) aneurysm size < 5 mm in addition to an irregular shape, multiple lesions, large dome/neck ratio, family history, or anterior communicating artery (ACoA) aneurysm or internal carotid artery (ICA) to posterior communicating artery (PCoA) aneurysm. The risks and benefits of the procedures were reviewed with all patients. If the patient rejected surgical treatment, they were followed up every 4 months, including an assessment of the aneurysm diameter and morphological changes on MRA, neurological status, and other medical conditions. Nonsurgical treatments, such as medications, were allowed as needed. The major end point in this study was rupture or growth of the UIA. If patients refused further follow-up or failed to return because of other medical conditions, the follow-up periods for these cases were calculated as those from their registration until the last day of follow-up.

Table 1 shows the baseline patient characteristics. Sixty-three patients (79.7%) had single UIAs, and 16 patients (20.3%) had multiple UIAs. Concomitant diseases included hypertension in 54 patients (68.4%), hyperlipidemia in 19 (24.1%), diabetes mellitus in 7 (8.9%), ischemic heart disease in 10 (12.6%), cerebral infarction in 12 (15.2%), HICH in 2 (2.5%), and SAH in 3 (3.8%). Fourteen patients (17.7%) were current smokers. Ten patients (12.6%) had a family history of intracranial aneurysm. Unruptured intracranial aneurysms were discovered for the following reasons: on brain checkups for headache, vertigo, numbness, and so forth in 62 patients (78.5%); in the course of examining cerebral infarction or HICH in 14 patients (17.7%); and in association with SAH in 3 patients (3.8%). The UIAs were located in the ICA in 25 cases (25.5%), the ACoA in 17 cases (17.3%), the anterior cerebral artery (ACA) in 4 cases (4.1%), the middle cerebral artery (MCA) in 45 cases (45.9%), and the vertebral or basilar artery in 7 cases (7.1%). The mean size of the UIAs was 4.9 ± 2.3 mm (range 2.0–13.1 mm).

TABLE 1:

Baseline characteristics in 79 patients with UIAs*

CharacteristicValue
patient information
no. of women (%)58 (73.4)
age in yrs
 mean ± SD73.9 ± 3.3
 median73
 range70–84
patients w/ multiple aneurysms (%)16 (20.3)
history of concomitant disease (%)
 hypertension54 (68.4)
 hyperlipidemia19 (24.1)
 diabetes mellitus7 (8.9)
 ischemic heart disease10 (12.6)
 cerebral infarction12 (15.2)
 HICH2 (2.5)
 SAH3 (3.8)
patients currently smoking (%)14 (17.7)
family history of intracranial aneurysm (%)10 (12.6)
aneurysm detection (%)
 on brain checkup62 (78.5)
 associated w/ exam for CI or HICH14 (17.7)
 associated w/ ruptured aneurysm3 (3.8)
aneurysm information
no. of aneurysms98
aneurysm location (%)
 ICA25 (25.5)
 ACoA17 (17.3)
 ACA4 (4.1)
 MCA45 (45.9)
 VA-BA7 (7.1)
mean aneurysm size in mm4.9 ± 2.3

CI = cerebral infarction; VA-BA = vertebral artery–basilar artery.

Data Analysis

Patients were categorized into age groups of 70–74 years and ≥ 75 years. Univariate analyses to assess categorical variables (for example, sex, age ≥ 75 years, aneurysm multiplicity, history of concomitant disease, antiplatelet use, current smoking status, family history of UIA, and aneurysm location) and aneurysm growth were compared using the chi-square test. Aneurysm diameter in terms of aneurysm growth was compared using the Mann-Whitney U-test. Variables with a p < 0.05 were retained as covariates and entered together into the multivariate Cox proportional-hazards regression model to identify independent predictive variables associated with future aneurysm growth. Differences were deemed statistically significant if p < 0.05. In the cases of aneurysm growth, follow-up periods were calculated from enrollment until the time of aneurysm growth detected on radiological examinations. The follow-up period was also expressed using the person-years method. The average annual risk of growth associated with UIAs was calculated by determining the number of first events of growth divided by the number of person-years of follow-up. The Kaplan-Meier product-limit method was used to estimate cumulative rates of growth.

Results

The mean duration of follow-up was 38.5 months (range 4–84 months), with a total of 250.2 patient-years of follow-up. Aneurysm rupture did not occur, but aneurysm growth was observed in 8 aneurysms (8 patients, all women). The characteristics of the patients with aneurysm growth are shown in Tables 2 and 3. Growth and bleb formation were observed in 3 aneurysms (3 patients). The 8 women with aneurysm growth ranged in age from 72 to 79 years (median 76 years), and the aneurysms were located in the MCA in 5 cases and in the ICA in 3 cases. The maximum diameter of the lesions on admission ranged from 3.2 to 14.7 mm (mean 6.3 mm). Four patients underwent clipping for the aneurysm growth. Four patients preferred continuous observation and did not develop SAH during this period. Therefore, only 4 aneurysms (4 patients) met the inclusion criteria and underwent clipping surgery.

TABLE 2:

Characteristics of the 8 patients with aneurysm growth*

Case No.Age, SexAneurysm LocationSize (mm)Bleb FormationDuration UntilGrowth (mos)Outcome
On AdmissionAfter Growth
179, FMCA10.112.848observation
279, FICA8.211.237observation
378, FMCA4.66.671observation
477, FICA14.716.9+27clipping
576, FICA4.86.2+11clipping
675, FMCA3.25.539clipping
774, FMCA4.46.512observation
872, FMCA4.35.1+31clipping

The patients had no aneurysms other than the one that grew.

TABLE 3:

Univariate analysis for risk factors associated with aneurysm growth aneurysm growth

Characteristicw/ Aneurysm Growthw/o Aneurysm Growthp Value
patient information
no. of patients871
females8500.04
age in yrs
 mean ± SD76.3 ± 2.773.6 ± 3.3
 median7772.5
patients aged 70–74 yrs246
patients aged ≥75 yrs6250.04
single aneurysm855
multiple aneurysms0160.15
history of concomitant disease
 hypertension747
 no hypertension1240.21
 hyperlipidemia118
 no hyperlipidemia7530.38
 diabetes mellitus16
 no diabetes mellitus7650.54
 ischemic heart disease011
 no ischemic heart disease8600.28
 cerebral infarction210
 no cerebral infarction6610.35
 antiplatelet use423
 no antiplatelet use4480.27
 HICH02
 no HICH8690.76
 SAH03
 no SAH8680.72
 currently smoking113
 not currently smoking7580.57
 family history of UIAs010
 no family history of UIAs8610.32
aneurysm information
no. of aneurysms890
mean aneurysm diameter in mm4.9 ± 2.35.7 ± 2.30.26
aneurysm location
 ICA or MCA862<0.001
 ACoA, ACA, or VA-BA028

The remaining 94 aneurysms (75 patients) were not surgically repaired. The proportion of women and the proportion of patients with an age ≥ 75 years were significantly larger in the group with aneurysm growth than in the group without (p = 0.04 for both; Table 3). There was no significant difference in the proportion of patients with hypertension, hyperlipidemia, diabetes mellitus, ischemic heart disease, cerebral infarction, antiplatelet use, HICH, SAH, current smoking, or family history of UIA when comparing patients with and without aneurysm growth. Aneurysm location in the ICA or MCA was significantly more common in patients with aneurysm growth than in those without (p < 0.001). There was no significant difference in aneurysm diameter or multiplicity when comparing patients with and without aneurysm growth.

Since probability values for female sex, patient age ≥ 75 years, and ICA or MCA aneurysm were less than 0.05, these variables were entered as independent variables into the multivariate Cox proportional-hazards regression model (Table 4). This analysis demonstrated that female sex was the only independent predictor of aneurysm growth (p = 0.0313, OR 2.3, 95% CI 1.3–30.2).

TABLE 4:

Independent predictive variables for aneurysm growth

FactorOR95% CIp Value
female sex2.31.3–30.20.0313
age ≥75 yrs−1.9 to 25.90.0901
ICA or MCA involvement−3.4 to 25.80.1302

In all patients, the 1-, 3-, 5-, and 7-year cumulative risks of aneurysm growth calculated using the Kaplan-Meier method were 2.8%, 7%, 15.3%, and 21.8%, respectively. In women, the 1-, 3-, 5-, and 7-year cumulative risks of aneurysm growth were 3.7%, 9%, 20.1%, and 28.3%, respectively.

Discussion

In the present study, univariate analysis suggested that female sex, patient age ≥ 75 years, and aneurysm location in the ICA or MCA were risk factors for the growth of UIAs in elderly patients. In a multivariate statistical analysis, the only independent risk factor for aneurysm growth was female sex. Our study demonstrated that aneurysms grew in 8 (10.1%) of 79 elderly patients. The growth rate of UIAs is expected to equal the rate in the present study (for example, 10.3%,2 10.1%18) or to increase (for example, 6.7%,25 6.4%16) as the general population ages. Several previous studies, including autopsy reports, have demonstrated that the incidence of SAH or UIAs was 3–4 times higher in patients older than 70 years and that the prevalence of aneurysms increases with aging.11,23,32 It is reasonable to suggest that factors associated with aging, such as prolonged exposure to hypertension, smoking, and atherosclerotic vessel degeneration, may contribute to an increased risk of aneurysm formation.5 Although other factors, such as race or geographic location, may be involved, the present study indicates that growth is important in the natural history of unruptured aneurysms in elderly patients.

In this study, female sex was the only significant independent risk factor for aneurysm growth. Specifically, women may have an odds ratio (OR) as high as 2.3 for aneurysm growth as compared with men. Female sex has been previously described as a risk factor for aneurysm growth.9,13 Aneurysm formation in women is thought to be attributable to hormonal factors.14 Since estrogen is known to inhibit tumor necrosis factor–α activity26 and the expression of adhesion molecules or chemo-attractants in vascular smooth muscle cells,7 reduced estrogen levels in postmenopausal women may predispose to a higher incidence of aneurysm development because of a diminution in the collagen content in cerebral arteries. Experimental studies support this hypothesis.12 In the present study, Kaplan-Meier analysis showed that the cumulative risk of growth at 1, 3, 5, and 7 years was 2.8%, 7%, 15.3%, and 21.8%, respectively, in all patients and 3.7%, 9%, 20.1%, and 28.3%, respectively, in women. This rapid increase in the proportion of aneurysms in elderly women displaying growth is another striking finding related to their natural course. This finding suggests that patients with nonsurgically treated aneurysms should be followed up over the long term to detect aneurysm growth that may require a modification in the treatment plan.

Patients 75 years of age or older had an increased risk of aneurysm growth according to univariate analyses. Our previous study suggested that surgical clipping of UIAs does not impair cognitive function and does relieve anxiety in patients ranging in age from 70 to 75 years,15 which is consistent with other data obtained in patients younger than 70 years.21,22 Among the 20 aneurysms (18 patients) that were excluded because of clipping surgery, 16 of them (15 patients) occurred in patients ranging in age from 70 to 74 years. Therefore, patient selection bias could have been a confounding factor in this study.

Univariate analysis in the present study suggested that an aneurysm location in the ICA or MCA was a risk factor for aneurysm growth. While some studies suggest that ICA or MCA aneurysms tend to grow,16,18 other studies have indicated no site predilection for aneurysm growth.2,3,9,13,25

The study of UIAs has strengthened the concept that chronic inflammation plays a significant role in aneurysm formation and potentially predisposes to aneurysm wall degeneration and rupture.29 Aspirin has inhibitory effects on several inflammatory mediators postulated to play a role in cerebral aneurysm formation. Findings in the International Study of Unruptured Intracranial Aneurysms (ISUIA) cohort suggest that frequent aspirin use may confer a protective effect against intracranial aneurysm rupture.8 In the present study, antiplatelet use was not associated with the growth of UIAs in elderly patients. However, further investigation is needed to confirm the effects of antiplatelet agents on aneurysm formation and growth.

This study has several limitations. First, because it was not a randomized study, patient selection bias cannot be ruled out. Our single-center study demonstrated that the incidence of UIAs in women was 73.4%. This rate is higher than those in multicenter prospective cohort studies or systematic reviews (for example, 66.5%,20 63.6%,25 59.7%19). Identification of female sex as a risk factor for aneurysm growth in a multivariate analysis was based on a population in which three-quarters of the patients had that risk factor. Second, because of the relatively small number of enrolled patients, the number of participants in this clinical study may not be large enough for appropriate statistical analysis. In addition, because of the relatively short follow-up period (mean 38.5 months) and the relatively small sample numbers, the validity of predictions based on the generation of Kaplan-Meier curves is uncertain. Recent studies in rats have suggested that statins and angiotensin receptor blockers have an inhibitory effect on the development of intracranial aneurysms.1,27 The effect of these agents in elderly patients warrants further investigation.

Conclusions

In summary, female sex is an independent risk factor for the growth of UIAs in elderly patients. In addition, a patient age ≥ 75 years and an aneurysm location in the ICA or MCA may require additional attention with periodic imaging during follow-up.

Disclosure

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. This work was supported by a grant from JSPS KAKENHI (23592103).

Author contributions to the study and manuscript preparation include the following. Conception and design: Kubo. Acquisition of data: Kubo. Analysis and interpretation of data: Kubo. Drafting the article: Kubo. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Kubo. Statistical analysis: Kubo. Administrative/technical/material support: Koji, Kashimura, Otawara. Study supervision: Ogawa, Ogasawara.

References

  • 1

    Aoki TKataoka HIshibashi RNakagami HNozaki KMorishita R: Pitavastatin suppresses formation and progression of cerebral aneurysms through inhibition of the nuclear factor ϰB pathway. Neurosurgery 64:3573662009

    • Search Google Scholar
    • Export Citation
  • 2

    Burns JDHuston J IIILayton KFPiepgras DGBrown RD Jr: Intracranial aneurysm enlargement on serial magnetic resonance angiography: frequency and risk factors. Stroke 40:4064112009

    • Search Google Scholar
    • Export Citation
  • 3

    Chien ALiang FSayre JSalamon NVillablanca PViñuela F: Enlargement of small, asymptomatic, unruptured intracranial aneurysms in patients with no history of subarachnoid hemorrhage: the different factors related to the growth of single and multiple aneurysms. Clinical article. J Neurosurg 119:1901972013

    • Search Google Scholar
    • Export Citation
  • 4

    Chmayssani MRebeiz JGRebeiz TJBatjer HHBendok BR: Relationship of growth to aneurysm rupture in asymptomatic aneurysms ≤ 7 mm: a systematic analysis of the literature. Neurosurgery 68:116411712011

    • Search Google Scholar
    • Export Citation
  • 5

    Chung RYCarter BSNorbash ABudzik RPutnam COgilvy CS: Management outcomes for ruptured and unruptured aneurysms in the elderly. Neurosurgery 47:8278332000

    • Search Google Scholar
    • Export Citation
  • 6

    Ferns SPSprengers MEvan Rooij WJvan den Berg RVelthuis BKde Kort GA: De novo aneurysm formation and growth of untreated aneurysms: a 5-year MRA follow-up in a large cohort of patients with coiled aneurysms and review of the literature. Stroke 42:3133182011

    • Search Google Scholar
    • Export Citation
  • 7

    Ferreri NR: Estrogen-TNF interactions and vascular inflammation. Am J Physiol Heart Circ Physiol 292:H2566H25692007

  • 8

    Hasan DMMahaney KBBrown RD JrMeissner IPiepgras DGHuston J: Aspirin as a promising agent for decreasing incidence of cerebral aneurysm rupture. Stroke 42:315631622011

    • Search Google Scholar
    • Export Citation
  • 9

    Inoue TShimizu HFujimura MSaito ATominaga T: Annual rupture risk of growing unruptured cerebral aneurysms detected by magnetic resonance angiography. Clinical article. J Neurosurg 117:20252012

    • Search Google Scholar
    • Export Citation
  • 10

    Ishibashi TMurayama YUrashima MSaguchi TEbara MArakawa H: Unruptured intracranial aneurysms: incidence of rupture and risk factors. Stroke 40:3133162009

    • Search Google Scholar
    • Export Citation
  • 11

    Iwamoto HKiyohara YFujishima MKato INakayama KSueishi K: Prevalence of intracranial saccular aneurysms in a Japanese community based on a consecutive autopsy series during a 30-year observation period. The Hisayama study. Stroke 30:139013951999

    • Search Google Scholar
    • Export Citation
  • 12

    Jamous MANagahiro SKitazato KTTamura TKuwayama KSatoh K: Role of estrogen deficiency in the formation and progression of cerebral aneurysms. Part II: experimental study of the effects of hormone replacement therapy in rats. J Neurosurg 103:105210572005

    • Search Google Scholar
    • Export Citation
  • 13

    Juvela SPoussa KPorras M: Factors affecting formation and growth of intracranial aneurysms: a long-term follow-up study. Stroke 32:4854912001

    • Search Google Scholar
    • Export Citation
  • 14

    Kongable GLLanzino GGermanson TPTruskowski LLAlves WMTorner JC: Gender-related differences in aneurysmal subarachnoid hemorrhage. J Neurosurg 84:43481996

    • Search Google Scholar
    • Export Citation
  • 15

    Kubo YOgasawara KKashimura HOtawara YKakino SSugawara A: Cognitive function and anxiety before and after surgery for asymptomatic unruptured intracranial aneurysms in elderly patients. World Neurosurg 73:3503532010

    • Search Google Scholar
    • Export Citation
  • 16

    Matsubara SHadeishi HSuzuki AYasui NNishimura H: Incidence and risk factors for the growth of unruptured cerebral aneurysms: observation using serial computerized tomography angiography. J Neurosurg 101:9089142004

    • Search Google Scholar
    • Export Citation
  • 17

    Matsumoto EMasuzawa TNakamura Y: Long-term outcome of unruptured cerebral aneurysms. J Epidemiol 13:2892952003

  • 18

    Miyazawa NAkiyama IYamagata Z: Risk factors for growth of unruptured intracranial aneurysms: follow-up study by serial 0.5-T magnetic resonance angiography. Neurosurgery 58:104710532006

    • Search Google Scholar
    • Export Citation
  • 19

    Morita AFujiwara SHashi KOhtsu HKirino T: Risk of rupture associated with intact cerebral aneurysms in the Japanese population: a systematic review of the literature from Japan. J Neurosurg 102:6016062005

    • Search Google Scholar
    • Export Citation
  • 20

    Morita AKirino THashi KAoki NFukuhara SHashimoto N: The natural course of unruptured cerebral aneurysms in a Japanese cohort. N Engl J Med 366:247424822012

    • Search Google Scholar
    • Export Citation
  • 21

    Otawara YOgasawara KKubo YTomitsuka NWatanabe MOgawa A: Anxiety before and after surgical repair in patients with asymptomatic unruptured intracranial aneurysm. Surg Neurol 62:28312004

    • Search Google Scholar
    • Export Citation
  • 22

    Otawara YOgasawara KOgawa AYamadate K: Cognitive function before and after surgery in patients with unruptured intracranial aneurysm. Stroke 36:1421432005

    • Search Google Scholar
    • Export Citation
  • 23

    Sacco RLWolf PABharucha NEMeeks SLKannel WBCharette LJ: Subarachnoid and intracerebral hemorrhage: natural history, prognosis, and precursive factors in the Framingham Study. Neurology 34:8478541984

    • Search Google Scholar
    • Export Citation
  • 24

    Shinohara YNagayama MOrigasa H: Postpublication external review of the Japanese Guidelines for the Management of Stroke 2004. Stroke 40:143914432009

    • Search Google Scholar
    • Export Citation
  • 25

    Sonobe MYamazaki TYonekura MKikuchi H: Small unruptured intracranial aneurysm verification study: SUAVe study, Japan. Stroke 41:196919772010

    • Search Google Scholar
    • Export Citation
  • 26

    Srivastava SWeitzmann MNCenci SRoss FPAdler SPacifici R: Estrogen decreases TNF gene expression by blocking JNK activity and the resulting production of c-Jun and JunD. J Clin Invest 104:5035131999

    • Search Google Scholar
    • Export Citation
  • 27

    Tamura TJamous MAKitazato KTYagi KTada YUno M: Endothelial damage due to impaired nitric oxide bioavailability triggers cerebral aneurysm formation in female rats. J Hypertens 27:128412922009

    • Search Google Scholar
    • Export Citation
  • 28

    Tsutsumi KUeki KMorita AKirino T: Risk of rupture from incidental cerebral aneurysms. J Neurosurg 93:5505532000

  • 29

    Tulamo RFrösen JPaetau ASeitsonen SHernesniemi JNiemelä M: Lack of complement inhibitors in the outer intracranial artery aneurysm wall associates with complement terminal pathway activation. Am J Pathol 177:322432322010

    • Search Google Scholar
    • Export Citation
  • 30

    Vlak MHRinkel GJGreebe PAlgra A: Risk of rupture of an intracranial aneurysm based on patient characteristics: a case-control study. Stroke 44:125612592013

    • Search Google Scholar
    • Export Citation
  • 31

    Wermer MJvan der Schaaf ICAlgra ARinkel GJ: Risk of rupture of unruptured intracranial aneurysms in relation to patient and aneurysm characteristics: an updated meta-analysis. Stroke 38:140414102007

    • Search Google Scholar
    • Export Citation
  • 32

    Yamashita KKashiwagi SKato STakasago TIto H: Cerebral aneurysms in the elderly in Yamaguchi, Japan. Analysis of the Yamaguchi Data Bank of Cerebral Aneurysm from 1985 to 1995. Stroke 28:192619311997

    • Search Google Scholar
    • Export Citation

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Article Information

Address correspondence to: Yoshitaka Kubo, M.D., Ph.D., Department of Neurosurgery, Iwate Medical University, 19-1 Uchimaru, Morioka 020-8505, Japan. email: yokubo@iwate-med.ac.jp.

Please include this information when citing this paper: published online June 27, 2014; DOI: 10.3171/2014.5.JNS132048.

© AANS, except where prohibited by US copyright law.

Headings

References

  • 1

    Aoki TKataoka HIshibashi RNakagami HNozaki KMorishita R: Pitavastatin suppresses formation and progression of cerebral aneurysms through inhibition of the nuclear factor ϰB pathway. Neurosurgery 64:3573662009

    • Search Google Scholar
    • Export Citation
  • 2

    Burns JDHuston J IIILayton KFPiepgras DGBrown RD Jr: Intracranial aneurysm enlargement on serial magnetic resonance angiography: frequency and risk factors. Stroke 40:4064112009

    • Search Google Scholar
    • Export Citation
  • 3

    Chien ALiang FSayre JSalamon NVillablanca PViñuela F: Enlargement of small, asymptomatic, unruptured intracranial aneurysms in patients with no history of subarachnoid hemorrhage: the different factors related to the growth of single and multiple aneurysms. Clinical article. J Neurosurg 119:1901972013

    • Search Google Scholar
    • Export Citation
  • 4

    Chmayssani MRebeiz JGRebeiz TJBatjer HHBendok BR: Relationship of growth to aneurysm rupture in asymptomatic aneurysms ≤ 7 mm: a systematic analysis of the literature. Neurosurgery 68:116411712011

    • Search Google Scholar
    • Export Citation
  • 5

    Chung RYCarter BSNorbash ABudzik RPutnam COgilvy CS: Management outcomes for ruptured and unruptured aneurysms in the elderly. Neurosurgery 47:8278332000

    • Search Google Scholar
    • Export Citation
  • 6

    Ferns SPSprengers MEvan Rooij WJvan den Berg RVelthuis BKde Kort GA: De novo aneurysm formation and growth of untreated aneurysms: a 5-year MRA follow-up in a large cohort of patients with coiled aneurysms and review of the literature. Stroke 42:3133182011

    • Search Google Scholar
    • Export Citation
  • 7

    Ferreri NR: Estrogen-TNF interactions and vascular inflammation. Am J Physiol Heart Circ Physiol 292:H2566H25692007

  • 8

    Hasan DMMahaney KBBrown RD JrMeissner IPiepgras DGHuston J: Aspirin as a promising agent for decreasing incidence of cerebral aneurysm rupture. Stroke 42:315631622011

    • Search Google Scholar
    • Export Citation
  • 9

    Inoue TShimizu HFujimura MSaito ATominaga T: Annual rupture risk of growing unruptured cerebral aneurysms detected by magnetic resonance angiography. Clinical article. J Neurosurg 117:20252012

    • Search Google Scholar
    • Export Citation
  • 10

    Ishibashi TMurayama YUrashima MSaguchi TEbara MArakawa H: Unruptured intracranial aneurysms: incidence of rupture and risk factors. Stroke 40:3133162009

    • Search Google Scholar
    • Export Citation
  • 11

    Iwamoto HKiyohara YFujishima MKato INakayama KSueishi K: Prevalence of intracranial saccular aneurysms in a Japanese community based on a consecutive autopsy series during a 30-year observation period. The Hisayama study. Stroke 30:139013951999

    • Search Google Scholar
    • Export Citation
  • 12

    Jamous MANagahiro SKitazato KTTamura TKuwayama KSatoh K: Role of estrogen deficiency in the formation and progression of cerebral aneurysms. Part II: experimental study of the effects of hormone replacement therapy in rats. J Neurosurg 103:105210572005

    • Search Google Scholar
    • Export Citation
  • 13

    Juvela SPoussa KPorras M: Factors affecting formation and growth of intracranial aneurysms: a long-term follow-up study. Stroke 32:4854912001

    • Search Google Scholar
    • Export Citation
  • 14

    Kongable GLLanzino GGermanson TPTruskowski LLAlves WMTorner JC: Gender-related differences in aneurysmal subarachnoid hemorrhage. J Neurosurg 84:43481996

    • Search Google Scholar
    • Export Citation
  • 15

    Kubo YOgasawara KKashimura HOtawara YKakino SSugawara A: Cognitive function and anxiety before and after surgery for asymptomatic unruptured intracranial aneurysms in elderly patients. World Neurosurg 73:3503532010

    • Search Google Scholar
    • Export Citation
  • 16

    Matsubara SHadeishi HSuzuki AYasui NNishimura H: Incidence and risk factors for the growth of unruptured cerebral aneurysms: observation using serial computerized tomography angiography. J Neurosurg 101:9089142004

    • Search Google Scholar
    • Export Citation
  • 17

    Matsumoto EMasuzawa TNakamura Y: Long-term outcome of unruptured cerebral aneurysms. J Epidemiol 13:2892952003

  • 18

    Miyazawa NAkiyama IYamagata Z: Risk factors for growth of unruptured intracranial aneurysms: follow-up study by serial 0.5-T magnetic resonance angiography. Neurosurgery 58:104710532006

    • Search Google Scholar
    • Export Citation
  • 19

    Morita AFujiwara SHashi KOhtsu HKirino T: Risk of rupture associated with intact cerebral aneurysms in the Japanese population: a systematic review of the literature from Japan. J Neurosurg 102:6016062005

    • Search Google Scholar
    • Export Citation
  • 20

    Morita AKirino THashi KAoki NFukuhara SHashimoto N: The natural course of unruptured cerebral aneurysms in a Japanese cohort. N Engl J Med 366:247424822012

    • Search Google Scholar
    • Export Citation
  • 21

    Otawara YOgasawara KKubo YTomitsuka NWatanabe MOgawa A: Anxiety before and after surgical repair in patients with asymptomatic unruptured intracranial aneurysm. Surg Neurol 62:28312004

    • Search Google Scholar
    • Export Citation
  • 22

    Otawara YOgasawara KOgawa AYamadate K: Cognitive function before and after surgery in patients with unruptured intracranial aneurysm. Stroke 36:1421432005

    • Search Google Scholar
    • Export Citation
  • 23

    Sacco RLWolf PABharucha NEMeeks SLKannel WBCharette LJ: Subarachnoid and intracerebral hemorrhage: natural history, prognosis, and precursive factors in the Framingham Study. Neurology 34:8478541984

    • Search Google Scholar
    • Export Citation
  • 24

    Shinohara YNagayama MOrigasa H: Postpublication external review of the Japanese Guidelines for the Management of Stroke 2004. Stroke 40:143914432009

    • Search Google Scholar
    • Export Citation
  • 25

    Sonobe MYamazaki TYonekura MKikuchi H: Small unruptured intracranial aneurysm verification study: SUAVe study, Japan. Stroke 41:196919772010

    • Search Google Scholar
    • Export Citation
  • 26

    Srivastava SWeitzmann MNCenci SRoss FPAdler SPacifici R: Estrogen decreases TNF gene expression by blocking JNK activity and the resulting production of c-Jun and JunD. J Clin Invest 104:5035131999

    • Search Google Scholar
    • Export Citation
  • 27

    Tamura TJamous MAKitazato KTYagi KTada YUno M: Endothelial damage due to impaired nitric oxide bioavailability triggers cerebral aneurysm formation in female rats. J Hypertens 27:128412922009

    • Search Google Scholar
    • Export Citation
  • 28

    Tsutsumi KUeki KMorita AKirino T: Risk of rupture from incidental cerebral aneurysms. J Neurosurg 93:5505532000

  • 29

    Tulamo RFrösen JPaetau ASeitsonen SHernesniemi JNiemelä M: Lack of complement inhibitors in the outer intracranial artery aneurysm wall associates with complement terminal pathway activation. Am J Pathol 177:322432322010

    • Search Google Scholar
    • Export Citation
  • 30

    Vlak MHRinkel GJGreebe PAlgra A: Risk of rupture of an intracranial aneurysm based on patient characteristics: a case-control study. Stroke 44:125612592013

    • Search Google Scholar
    • Export Citation
  • 31

    Wermer MJvan der Schaaf ICAlgra ARinkel GJ: Risk of rupture of unruptured intracranial aneurysms in relation to patient and aneurysm characteristics: an updated meta-analysis. Stroke 38:140414102007

    • Search Google Scholar
    • Export Citation
  • 32

    Yamashita KKashiwagi SKato STakasago TIto H: Cerebral aneurysms in the elderly in Yamaguchi, Japan. Analysis of the Yamaguchi Data Bank of Cerebral Aneurysm from 1985 to 1995. Stroke 28:192619311997

    • Search Google Scholar
    • Export Citation

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