The Natural History of Cerebral Aneurysms

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CHAPTER 360 The Natural History of Cerebral Aneurysms

The natural history of any disease is defined as the outcome of the disease in the absence of any intervention. Knowledge of the natural history can therefore allow the physician to evaluate the safety and effectiveness of different treatment options.

In the mid-20th century, the natural history of ruptured cerebral aneurysms was a topic of intensive focus by neurosurgeons, neurologists, and epidemiologists. This interest was related to the high mortality and morbidity associated with the treatment of aneurysms and the desire by clinicians to identify which patients were at greatest risk of suffering a rehemorrhage. With advances in angiographic methods and anesthesia technique and introduction of the operative microscope, the risk associated with treatment decreased, and almost all patients were considered candidates for direct surgical repair. Consequently, interest in defining the natural history waned. However, with the advent of computed tomography (CT) and magnetic resonance imaging (MRI) and the increased ability to detect intact aneurysms, neurosurgeons, neurologists, and epidemiologists again became interested in more accurately defining the natural history with an increased focus on unruptured aneurysms. Most recently, the introduction of cerebral interventional techniques has made the need for defining the natural history more compelling, especially for comparison of the natural history with the long-term outcome of interventionally treated aneurysms.

This chapter discusses the natural history of both unruptured and ruptured cerebral aneurysms. When evaluating the natural history of cerebral aneurysms, intact and ruptured aneurysms should be considered separately because epidemiologic studies have determined that the natural history of unruptured and ruptured cerebral aneurysms is different.

Natural History of Unruptured Aneurysms

Intact or unruptured intracranial aneurysms (UIAs) are aneurysms with no recent or remote history of subarachnoid hemorrhage (SAH). Management of these patients is controversial because the natural history from the current studies is unclear.¹ The treating physician must evaluate not only the aneurysm but also patient factors such as age, medical condition, and family history. Such information allows the neurosurgeon to make a calculated judgment about the lifetime risk associated with UIAs in comparison to the risk related to treatment. For example, a relatively benign natural history would favor conservative therapy (i.e., observation), particularly in the older population. In contrast, a more malignant natural history in a younger patient would make intervention more urgent. Life tables, which are based on population studies, are an estimate of life expectancy (Fig. 360-1), but an individual may vary considerably from these averages. Therefore, assessment of an individual patient’s risk involves evaluating not only the likelihood of rupture of an intact aneurysm but also the patient’s life expectancy.

FIGURE 360-1 Life expectancy by age.

(From Mon Vit Stat Rep 1997;45:18.)

Prevalence of Unruptured Aneurysms

There is considerable variation in the reported prevalence of UIAs (Table 360-1). This variation can be attributed to multiple factors, such as the nature of the study (i.e., retrospective or prospective), the mechanism and accuracy of detection (i.e., autopsy, CT, computed tomographic angiography [CTA], MRI, magnetic resonance angiography [MRA], catheter angiography), the interest and focus of the investigator (i.e., pathologist, neuropathologist, or vascular neuropathologist), and definition of a cerebral aneurysm (i.e., 1-mm versus larger expansion at a vessel bifurcation). In addition, the characteristics of the population, such as age (e.g., elderly) and nationality (i.e., Finnish and Japanese), will influence the prevalence. Lifestyle (i.e., tobacco use) and environmental factors (alcohol) may also explain variations in reported prevalence rates of UIAs. Finally, it is becoming more evident that genetic influences are involved in aneurysm formation (for further discussion, please see Chapter 362).

TABLE 360-1 Prevalence of Unruptured Aneurysms

	NO. OF PATIENTS	PREVALENCE
Autopsy
Fox et al., 1983	164,764	0.8%
Radiology
Pre-CT era: Winn et al., 1978	4658	0.65%
Post-CT era: Ujie et al., 1993	1612	2.7%

CT, computed tomography.

Rinkel and colleagues comprehensively reviewed 23 studies including more than 50,000 patients and noted a prevalence, on average, of 0.4% in retrospective autopsy studies, 3.6% in prospective autopsy studies, 3.7% in retrospective angiography studies, and 6.0% in prospective angiography studies.² As just noted, this variation can be attributed to the nature of the population studied and the mechanisms used to document the presence of a UIA. Most of the angiographic studies analyzed by Rinkel and coworkers originated in the post-CT/MRI era, which may have skewed the prevalence of UIAs upward.² In the post-CT/MRI era, angiography is used mainly for patients with vascular disease and therefore encompasses an older segment of the patient population. In contrast, a pre-CT (see Table 360-1) study based on angiography revealed a prevalence of 0.65%. In the pre-CT era, angiography was used more liberally; a broader segment of the population was surveyed and therefore may be more representative of the true prevalence of UIAs.

In summary, the prevalence of UIAs has been found to vary considerably from less than 1% to as high as 9%. This variation appears to be related to a number of factors, such as methodologies and techniques used in data collection, environmental influences, patient characteristics, and genetic factors.

Rupture Rate of Unruptured Aneurysms

Despite intensive investigations, the incidence of SAH in patients with UIAs is not perfectly defined, as shown in the following studies (summarized in Table 360-2):

• Locksley monitored 34 patients with 34 UIAs for almost 4 years and noted that 9 patients suffered an SAH, for a yearly rupture rate of 7%.³ However, all the patients described in Locksley’s report had symptomatic aneurysms, which may have a high risk for hemorrhage (see the later section “Symptomatic Aneurysms”).

• Zacks and colleagues reported data from 10 patients with 12 incidental aneurysms. No patients suffered an SAH; however, 5 of the UIAs were smaller than 3 mm, 3 were 3 to 6 mm, and 1 was 10 mm in diameter.⁴ One of the patients died of a pulmonary embolus 2 months after treatment. Three of the 9 survivors underwent follow-up angiography 12 to 16 months later, and no change in appearance of the aneurysm was noted. These 9 patients were observed for a mean of 37 months (maximum, 90 months), during which no SAH occurred.

• Heiskanen presented a follow-up review of 61 patients with 129 unruptured aneurysms who had previously been treated for ruptured aneurysms and were observed for 10 years.⁵ During this period 7 patients bled from a previously unruptured aneurysm, for a rupture rate of approximately 1.1% per year.

• Wiebers and coworkers reported a selected group of 65 patients with 81 unruptured intracranial saccular aneurysms who did not undergo surgery.⁶ In 8 of the 65 patients, SAH subsequently developed as a result of rupture of an aneurysm over a mean follow-up interval of slightly more than 8 years, for an approximate rupture rate of 1%. This study was particularly important in that it was first to stratify the lesions by size and to assess the value of aneurysm size in the risk for rupture. Wiebers and colleagues reported a zero risk of rupture for aneurysms less than 10 mm in diameter and a risk of 1.7% per year for aneurysms larger than 10 mm.⁶ Their data also suggested that patients with multiple aneurysms had an increased risk for rupture.

• In 1983, Winn and coauthors reported the long-term (10-year) outcomes of patients with multiple aneurysms.⁷ All patients had a history of SAH and surgical treatment of ruptured aneurysm. The investigators evaluated the fate of the intact aneurysms and found approximately a 1% per year rate of hemorrhage.

• 1987, Wiebers and associates further reported their long-term follow-up of 130 patients with 161 unruptured aneurysms.⁸ This study also included follow-up of the patients from their earlier analysis and confirmed their previous observations: unruptured saccular aneurysms less than 10 mm in diameter have a very low probability of subsequent rupture, with no patients who had aneurysms less than 10 mm in diameter rebleeding. However, 15 of the 59 aneurysms larger than 10 mm ruptured, for a rupture rate of approximately 2% per year for that group.

• Easton and coworkers speculated on the natural history by assuming a prevalence of 5% (based on autopsy rates) and a population-based incidence of aneurysmal SAH of 10 per 100,000 persons per year.⁹ These investigators concluded that most aneurysms never rupture. However, their prevalence rate of 5% is high (see Table 360-1), which may have overrepresented the number of patients at risk and thereby skewed the risk for rupture downward.

• In 1993, Juvela and colleagues reported 181 aneurysms in 142 patients with a mean follow-up of 166.8 months.¹⁰ They found that the risk for rupture was 1.4% annually, a value based on the first 27 aneurysm ruptures during the follow-up period. If considering aneurysms rather than patients, the annual risk was 1.1% (27 events during 2434 aneurysm-years). This population was somewhat different from that of Wiebers and colleagues in that 92% of the patients had suffered a previous SAH from another aneurysm but was similar to the population studied by Winn and associates.⁷

• In 1993, Asari and Ohmoto reported on 54 patients with 72 unruptured cerebral aneurysms.¹¹ Twenty-two patients died during the observation period, which averaged 43.7 months. The 5-year survival rate was 56%. Aneurysms ruptured in 11 patients (20.4%), 10 of whom died without undergoing surgery. The annual bleeding rate was 1.9%, and the average size of the 11 ruptured aneurysms was 13.1 mm. In 4 patients, however, bleeding occurred in unruptured cerebral aneurysms 4 to 5 mm in size.¹¹

• Taylor and coworkers reported a large study involving 20,767 Medicare patients who were admitted to a hospital and in whom unruptured cerebral aneurysms were diagnosed.¹² The average age of these patients was 73.8 years, and 70% were women. In this study, 2648 patients were excluded from follow-up because of a concurrent diagnosis of SAH or in-hospital death, and therefore 18,119 patients were identified with the diagnosis of unruptured cerebral aneurysm. These patients were divided into two populations. Group 1 (7113 patients) was composed of patients with UIA as a primary diagnosis, whereas group 2 (11,066 patients) consisted of patients with UIA as a secondary diagnosis. After 2.5 years of follow-up, the risk for hemorrhage was 2% per year for the first group and 1.3% for the second group.¹²

• In 1997, Yasui and colleagues reported the results of a follow-up study of 303 unruptured aneurysms in 234 patients.¹³ Single aneurysms were present in 171 patients and multiple aneurysms in 63. The mean follow-up period was 75 months (range, 3 to 270 months). Of the 234 patients, 132 (56.4%) survived, 59 (25.2%) died of other diseases, 9 (3.8%) underwent surgery, and 34 (14.5%) bled from unruptured aneurysms, which was fatal in 18 of the patients. The annual rupture rate was 2.3%.¹³ The cumulative probability of rupture was significantly higher for patients with multiple aneurysms than for those with single aneurysms.

• The International Study of Unruptured Intracranial Aneurysms (ISUIA), a study consisting of several groups of patients with relevance to the natural history of UIAs, divided 1449 patients with 1937 UIAs into two groups: 727 patients (group 1) who had no previous history of SAH and 722 patients (group 2) who had a history of SAH.¹⁴ The mean duration of follow-up was 8.3 years, with a total of 12,023 patient-years of follow-up. Of the 1449 patients, 32 had documented aneurysmal ruptures. In group 1, the cumulative rate of rupture was 0.05% per year for aneurysms less than 10 mm and about 1% for those larger than 10 mm in diameter. Aneurysms larger than 25 mm had a 6% rupture rate in the first year. In group 2, the cumulative rate of rupture was about 0.5% per year for lesions smaller than 10 mm and about 1% for those larger than 10 mm in diameter. In group 1, in addition to size, location was related to hemorrhage risk, with basilar tip, vertebral-basilar, posterior cerebral, and posterior communicating artery aneurysms having a higher risk for rupture. In group 2, only location (i.e., basilar tip) and increasing age predicted an increased rate of hemorrhage.

TABLE 360-2 Risk of Rupture of Unruptured Aneurysms

The strengths of the ISUIA include its multicenter design, which minimizes referral and treatment bias, and its size, which provides robust statistical power to formulate conclusions.¹⁴ The study has, however, been challenged on a number of points that are largely related to selection bias, the retrospective nature of the study, and the inclusion of patients with cavernous aneurysms in the study population.^1,¹⁵^–¹⁷ Cavernous carotid aneurysms are known to have a lower risk for hemorrhage.¹⁸ However, after excluding intracavernous aneurysms, the investigators concluded that the rate of hemorrhage was only slightly increased from 0.05% to 0.066% per year for small aneurysms and from 0.95% to 1.38% for large aneurysms.¹⁹

The most significant criticism of the study is related to the possibility of selection bias. Does the population studied truly represent a population of patients with UIA, or has some selection bias created a population with an inherently lower risk for rupture? This concern is particularly significant because selection bias cannot be corrected with any statistical methods. In regard to selection bias, all patients were selected for observation or surgery after consultation with a neurosurgeon.^1,¹⁵^–¹⁷ ^,20 If it is assumed that most experienced neurosurgeons have an intuitive concept of what constitutes an aneurysm at high risk for rupture (e.g., size, configuration, family history), it is reasonable to presume that high-risk patients were treated and removed from the study pool. Removal of these high-risk patients could potentially skew the risk for rupture downward. Indeed, a calculation by Winn and associates based on the low rupture rate in the ISUIA project resulted in an extraordinary high UIA prevalence rate of 16% to 33%.^1,²⁰ This calculated prevalence rate derived from ISUIA data is several magnitudes larger than the reported prevalence rates of UIAs² (see Table 360-1).

• Juvela and coworkers studied 142 Finnish patients with UIAs and a mean follow-up duration of 19.7 years.²¹ Of the original population, 131 (92%) had previously experienced SAH, were found to have multiple aneurysms, and had only the offending lesion clipped. The investigators found an annual incidence of about 1.3% (95% confidence interval [CI], 0.9% to 1.7%). Seventy percent of the aneurysms that ruptured were also smaller than 6 mm, and the aneurysm rupture rate was found to increase linearly with lesion size. The study by Juvela and coworkers²¹ is unique because the confined catchment area and stable Finnish population made a long and a high follow-up percentage possible.¹⁶

As with other studies, the analysis by Juvela and colleagues ²¹ has limitations. Although the study generally lacked selection bias, the aneurysm population was derived from 30 to 50 years ago, before the introduction of imaging techniques, and it may represent a different group of patients than seen today.²² In addition, the data were compiled from a single center with the inherent single-center bias.²³ A potential does exists for genetic bias because the Finnish population is known to have a higher prevalence of UIAs, a higher incidence of SAH (13 to 16 per 100,000 persons per year^24,²⁵) than in other Western countries (10/100,000 persons per year²⁶), and a different aneurysm distribution (higher frequency of middle cerebral artery aneurysms).^17,²⁷ Most importantly, with regard to the validity of the natural history of UIAs, the study had insufficient numbers of truly incidental asymptomatic aneurysms; only 5 (4%) of the 142 patients had no previous history of SAH.²¹ The patients in the study by Juvela and associates²¹ were similar to those reported by Winn and coauthors⁷ in that the study involved long-term follow-up of patients with multiple aneurysm who suffered an SAH and had the offending lesion clipped, as well as similar to the patients in group 2 of the ISUIA study. All three studies reported a rate of rupture approximating 1%.

• Tsutsumi and colleagues reported 62 patients with UIAs treated conservatively at locations not related to the cavernous sinus.²⁸ The mean follow-up was 4.3 years. Seven patients (11.3%) experienced SAH confirmed by CT. The 5- and 10-year cumulative risk for CT-confirmed SAH calculated by the Kaplan-Meier method was 7.5% and 22.1%, respectively, for total cases; 33.5% and 55.9%, respectively, for large (>10 mm) aneurysms; and 4.5% and 13.9%, respectively, for small (<10 mm) aneurysms.²⁸

However, this study by Tsutsumi and colleagues ²⁸ must be interpreted with caution because the sample population was small and the power of the statistical analysis is therefore in question. Moreover, the follow-up period was relatively short, and the data were derived from a single center, with the associated single-center bias. The patients were obtained from a population of patients undergoing cerebral angiography who were older (mean age, 70.8 years) and had a high concomitant rate of ischemic and hemorrhagic events.

In summary, the yearly rupture rate of UIAs remains to be defined precisely, but in general it is 1% for aneurysms approximately 10 mm in size.

Factors Associated with Rupture

As already noted, the rate of rupture of UIAs may be affected by multiple factors related to the aneurysm or the patient.

For example, in 1974 Mount and Brisman reviewed 158 patients with unruptured, multiple aneurysms (which included the earlier study of Heiskanen and Marttila ³⁰) monitored for an average of 5 years and noted a bleeding rate of at least 2% per year.³⁰ Wiebers and associates also found that multiple aneurysms had a greater propensity for rupture than did solitary aneurysms.^6,⁸ This was consistent with the data from Winn and colleagues.⁷ Yasui and coworkers demonstrated an annual rupture rate of 6.8% in patients with multiple aneurysms and 1.9% in those with single UIAs.¹³ A meta-analysis by Rinkel and associates found that the risk for rupture was higher in patients with multiple aneurysms, with a 1.7 relative risk for rupture in patients with multiple lesions in comparison to those with an asymptomatic lesion.² In contrast, a study conducted in Helsinki by Juvela and colleagues with 2 decades of follow-up did not confirm a higher risk for SAH in patients with multiple UIAs.^10,²¹

In summary, most studies support the concept that multiple UIAs are associated with a higher risk for hemorrhage than solitary aneurysms are.

Aneurysm Growth

The report by Juvela and coauthors of patients harboring a UIA had a median follow-up period of 14 years and noted that aneurysms that subsequently ruptured (17 patients) displayed a significant increase in size.¹⁰ Among the 14 patients for whom angiographic follow-up was available and in whom there was no sign of rupture, no significant increase in aneurysm size was noted. Interestingly, growth was strongly associated with cigarette smoking (odds ratio [OR], 3.48; 95% CI, 1.14 to 10.64; P < .05).¹⁰ In contrast, Sampei and coworkers observed the growth of aneurysms between successive angiographic examinations in 25 patients and noted that rebleeding did not appear to be affected by the growth rate or by the initial size of the aneurysm.³¹ However, 11 of the patients were monitored for only less than 1 month.

In summary, the data in the literature are insufficient to conclusively document a relationship between aneurysm growth and risk for rupture.

Symptomatic Aneurysms

Symptomatic aneurysms are aneurysms accompanied by signs and symptoms related to the lesion, excluding clinical features related to SAH. The symptoms may be mild, such as headaches, or more severe, such as cranial nerve palsies and brainstem signs. The studies of Locksley ³ and Rinkel and colleagues² support the existence of a relationship between symptomatic UIAs and an increased propensity for rupture. In the Cooperative Aneurysm Study, 34 patients with symptomatic, unruptured aneurysms were observed for almost 4 years (47 months), and 26% died of SAH (≈7%/yr).³ This rate was significantly higher than the rupture rate for incidental aneurysms (0.8%/yr). Rinkel and colleagues found that the relative risk for rupture of a symptomatic aneurysm was 8.2 times that of an asymptomatic lesion.² However, in a multivariate analysis by Wiebers and associates, no correlation could be found between risk for hemorrhage and symptoms.⁶ This was also the case for Juvela and coworkers, who found that the percentage of patients without SAH was 65% to 80% at 20 years of follow-up, which did not differ significantly when symptomatic and nonsymptomatic (i.e., incidental) aneurysms were compared.¹⁰

Excluding headaches as a symptom, the majority of symptomatic aneurysms are associated with cranial nerve III dysfunction and are therefore most likely located at the posterior communicating location. This location has been found to have a higher rate of rupture of UIAs.^14,³²^–³⁴ Moreover, to affect cranial nerve III function, a UIA must enlarge. Increased size has been demonstrated to be correlated with hemorrhage. Thus, the perception that symptomatic UIAs have an increased rate of rupture may be an epiphenomenon related to aneurysm location and size.

In summary, the data are equivocal on an association between symptoms and rupture in UIAs.

Patient Age

Increasing age has been thought to increase the risk for hemorrhage. Wier, in a comprehensive review of the literature, stated that the rate of aneurysm rupture progressively increases with age but that extreme old age is protective.³⁵ An increased risk for hemorrhage with increasing age was also demonstrated by Wiebers and colleagues, but only in patients whose aneurysm was 10 mm or larger.⁸ Juvela and coauthors noted that the only variable that tended to predict rupture was the age of the patient.^10,²¹ Age as a predictor of rupture was also demonstrated in the ISUIA,¹⁴ but just in patients with a history of SAH (group 2). However, a protective effect of age was suggested in the earlier autopsy data from McCormick,³⁶ as well as in a subsequent large population analysis by Taylor and colleagues of more than 20,000 elderly patients,¹² although the shortened life expectancy (see Fig. 360-1) of the moderately to extremely elderly (i.e., reduced duration of risk) may account for the suggestion of age serving as protection against rupture of UIAs.

In summary, most of the literature supports the concept of increasing age being associated with an increased risk for rupture.

Systemic Hypertension

The role of hypertension in aneurysm formation and rupture has been controversial. The concept of hypertension increasing the risk for hemorrhage makes intuitive sense. However, Stehbens, in a review of pathology data, concluded that no association exists between hypertension and SAH,^37,³⁸ and other studies have arrived at similar conclusions.^6,^8,^10,³⁹ In contrast, though, some investigators have found that hypertension increases the risk for SAH. For example, the study by Sacco and associates, which reviewed the data on 5184 residents of Framingham, Massachusetts, demonstrated a significantly higher risk for SAH in patients with hypertension.²³ Winn and colleagues described the long-term (7.7 years) outcome in patients with multiple aneurysms who had suffered an SAH and had their offending lesion directly clipped.⁷ Systemic hypertension was found to increase the risk for subsequent rupture of a previously intact UIA. Asari and Ohmoto analyzed data from 54 patients with 72 unruptured aneurysms and found that hypertension was significant in predicting future rupture.¹¹

In 1995, Taylor and colleagues described the demographics and prevalence of hypertension in 20,767 Medicare patients with unruptured aneurysms and compared these results with a random sample of the hospitalized Medicare population.¹² For patients with an unruptured cerebral aneurysm as the primary diagnosis, hypertension was found to be a significant risk factor for future SAH (risk ratio, 1.46; 95% CI, 1.01 to 2.11). A study by Inagawa found that the frequency of hypertension was increased in patients with UIAs but was not related to risk for rupture.⁴⁰

Strong support for hypertension being a risk factor comes from the remarkable prospective study by Sandvei and associates from one county in Norway in which 75,000 individuals were monitored for more than 2 decades. The authors found that hypertension was significantly overrepresented in patients subsequently suffering an aneurysmal SAH.⁴¹

In summary, recent data support an association between systemic hypertension and increased risk for rupture of UIAs.

Cigarette Smoking

Cigarette smoking has been statistically associated with the occurrence of aneurysmal SAH. In a multicenter study, prospective data revealed that patients with SAH reported current smoking rates 2.5 times higher than expected based on U.S. and European national surveys.⁴² Moreover, cigarette smoking was also associated with younger age at the onset of SAH (5 to 10 years younger, P < .0001).⁴³ Matsumoto and colleagues observed 123 patients with an unruptured cerebral aneurysm incidentally detected during investigation for other diseases.⁴³ Sixty-nine patients, shown to be free of cerebral aneurysms with MRA, served as a control population. Smoking significantly increased the risk for aneurysm formation and SAH, especially in women and younger patients.⁴³ In 2000, Qureshi and associates, in analyzing prospectively collected data from a multicenter clinical trial, found that smoking (OR, 2.2; 95% CI, 1.1 to 4.5) was independently associated with large aneurysms in patients with SAH. As noted previously, aneurysmal size is associated with risk for rupture of UIAs. The prospective study by Sandvei and colleagues found that past and current smokers had a significantly higher likelihood of having an aneurysmal SAH than nonsmokers did.⁴¹

In summary, the preponderance of the literature reports a strong association between cigarette smoking and an increased prevalence and risk for rupture of UIAs.

Alcohol, Diabetes Mellitus, and Metabolic Factors

Alcohol use and the presence of diabetes mellitus did not appear to be overly represented in 285 patients with UIA.⁴⁰ In contrast, alcohol use has been found to be associated with and diabetes to be protective of nonaneurysmal SAH.⁴⁴ The prospective study by Sandvei and associates revealed that high body mass was protective against aneurysmal SAH.⁴¹

Gender

It has long been recognized that cerebral aneurysms occur more frequently in females than in males.^36,^37,⁴⁵ With respect to gender and rupture rate, several studies suggest that female gender increases the risk for rupture. For example, the meta-analysis of nine studies by Rinkle and colleagues found a higher rupture rate in women, with a relative risk of 2.1.² In addition, Juvela and coworkers found that female gender was an independent risk factor for rupture of UIAs.²¹ However, in the large analysis of hospital data, Taylor and associates found that gender was not a predictor for risk of hemorrhage.¹²

In summary, women may have an increased likelihood for UIA rupture, but the data are inconclusive.

Genetic and Molecular Factors

A comprehensive discussion of the genetics of cerebral aneurysms is presented in Chapter 362. However, in brief, based on a number of observations,^46,⁴⁷ there is increasing evidence of a genetic role in the formation of cerebral aneurysms. Moreover, genetic and molecular factors may be associated with an increased rate of rupture of UIAs.⁴⁷^–⁵² For example, several diseases, such autosomal dominant polycystic kidney disease (ADPKD), Marfan’s disease, and Ehlers-Danlos syndrome, have been associated with an increased prevalence and rupture of UIAs.⁵³ Unruptured cerebral aneurysms have been found in 6% of patients with ADPKD and no family history of UIAs, a figure higher than in the non-ADPKD population.⁵⁴ In ADPKD patients with a family history of UIAs, the prevalence has been found to be 16%.⁵⁴ The latter patients also appear to have an increased risk for rupture of UIAs.⁵⁴

In similar fashion, patients who have more than one first-degree relative with a cerebral aneurysm have a risk of harboring a UIA as high as 4% to 25%.^46,^55,⁵⁶ The percentage of patients with a discernible family history of aneurysmal SAH may be miscalculated by a bedside interview,⁵⁷ and consequently, previous studies may have underestimated this genetic connection. Familial UIAs appear to rupture sooner, at a smaller size, and be located less frequently at the anterior communicating location.^46,^58,⁵⁹ Moreover, familial UIAs occur as multiple rather than single aneurysms. Further evidence of a genetic basis is the concordant presence of UIAs in monozygotic twins⁶⁰ and the higher rate of aneurysm formation and rupture in the Finnish and Japanese populations.⁶¹

In summary, there is an increasing body of evidence that genetic factors act in isolation or in combination with environmental influences to affect the formation and rupture rate of UIAs (see later).

Summary of the Natural History of Unruptured Aneurysms

In the future, the number of patients discovered to have UIAs will increase as the population ages and as the sensitivity of detection systems improves. In deciding on the management of patients with UIAs, the treating physician must be cognizant of the characteristics of the specific aneurysm and individual patient that can affect the natural history. Unfortunately, the precise rupture rate of UIAs remains unclear. However, the origin and natural history are affected by multifactorial influences. Aneurysm characteristics associated with rupture include aneurysm size, location, and multiplicity. Patient characteristics include age, sex, history of hypertension, smoking, and genetic factors.

Natural History of Ruptured Aneurysms

In contrast to the natural history of UIAs, which is still unclear, the natural history of ruptured aneurysms is better defined and based significantly on randomized trials comparing surgery with bed rest therapy.^3,⁶²^–⁶⁹ These trials stem from an era when the results of surgery and conservative therapy for ruptured aneurysms were equivocal.⁶²^–⁶⁴ The results from these various studies defined the natural history of ruptured cerebral aneurysms and are divided into two epochs: short term (hospitalization to 6 months after the initial SAH) and long term (after 6 months). Not to be ignored is the initial epoch or prehospital (or never hospitalized) period. This prehospital phase is frequently overlooked and can be documented only with population-based studies. Three percent to 18% of patients suffering an SAH die before hospitalization.^70,⁷¹ The variation in prehospital death rate may reflect the setting (urban versus rural), medical retrieval system, geography, rigor in analyzing prehospital deaths, or any combination of these factors. However, variation in the prehospital death rate may indicate the potential for improvement in the treatment of aneurysmal SAH.

Short-Term Outcome: Post-hospitalization Period to Six Months

For hospitalized SAH patients, mortality is associated with initial hemorrhage, rebleeding, related complications such as vasospasm and hydrocephalus, and medical complications.⁷⁰ The initial direct effects are the major cause of mortality, but rebleeding also makes a significant contribution.⁷⁰ Locksley provided another view of the natural history in his analysis of the survival of 830 conservatively treated patients after rupture of a single aneurysm (Fig. 360-2).³ Three populations were identified by curve-stripping technique: group 1 (9% of the population) had a half-life that was measured in hours. This segment of the SAH population represents grade V patients.⁷² The second group (47% of the population) had a half-life measured in days. These patients are probably representative of grade III patients. The last group, 43% of the population, had a half-life measured in months and represents patients with the best grade.

FIGURE 360-2 Survival after rupture of a single aneurysm. The percentage alive is plotted in red; the purple intercept and slope represent the best-grade patients (43% of the population), whose half-life is measured in months; the pink intercept and slope represent intermediate-grade patients (47% of the population), whose half-life is measured in weeks; and the green intercept and slope represent poor-grade patients (9% of the population), whose half-life is measured in hours. SAH, subarachnoid hemorrhage.

(Modified from Locksley HB. Natural history of subarachnoid hemorrhage, intracranial aneurysms and arteriovenous malformations. J Neurosurg. 1966;25:321-368.)

Factors Associated with Outcome after Aneurysm Rupture

In conservatively treated patients, multiple factors are associated with outcome after aneurysmal SAH aside from the initial hemorrhage.

Grade on Admission

As illustrated in Table 360-3, there is a strong statistical correlation between clinical grade on admission and mortality during the first 6 months after the initial hemorrhage.³⁴ This association was subsequently confirmed in a study by Philips and coworkers³⁹ and more recently by Lagares and colleagues.⁷³

TABLE 360-3 Hunt and Hess Grade on Admission Is Strongly Correlated (P < .001) with Mortality at 6 Months in Conservatively Managed Patients (N = 364)

GRADE	MORTALITY (%)
I	15
II	30
III	50
IV	65
V	95

(From Winn HR, Richardson AE, Jane JA. The long-term prognosis in untreated cerebral aneurysms: I. The incidence of late hemorrhage in cerebral aneurysm: a 10-year evaluation of 364 patients. Ann Neurol. 1977;1:358-370.).

Aneurysm Location

In addition to clinical grade on admission, aneurysm location is also associated with mortality as indicated in Table 360-4.³⁴ Thus, mortality at 6 months in conservatively treated patients was 34% to 39% after rupture of an anterior circulation aneurysm, approached 50% in patients with multiple aneurysms, and was a higher still (61%) with aneurysms arising from the posterior circulation.³⁴

TABLE 360-4 Aneurysm Location versus Mortality at 6 Months *

ANEURYSM LOCATION	MORTALITY (%)
ACA	33.7
PCA	36.6
MCA	39.3
Multiple	47.0
VBA	60.9

ACA, anterior communicating artery; MCA, middle cerebral artery; PCA, posterior communicating artery; VBA, vertebral-basilar arteries.

* The original population consisted of 719 patients with a single ruptured aneurysm.

Time after Hemorrhage

Time after hemorrhage is also correlated with mortality.⁷⁴ For patients seen immediately after their aneurysm ruptures, the likelihood of 1-month survival is approximately 40%. In contrast, if a patient is not seen for 24 hours, the likelihood of survival to 1 month is “improved” to 60%. Alternatively, if a patient does not come to medical attention for 7 days, the likelihood of survival to 1 month is almost 80%. The difference in survival is related to the high mortality during the initial period after SAH (see Fig. 360-2). The association between time after hemorrhage and survival is important to consider when evaluating individual patients, as well as when reviewing the results of treatment studies in the literature.

Molecular and Genetic Profiles

A variety of molecular factors have been investigated to determine whether their presence is associated with outcome. Leung and associates recently tested the hypothesis that the apolipoprotein E genotype (APOE4) would be expressed more frequently in patients with an unfavorable outcome. Apolipoprotein E is a known “injury factor.”⁷⁵ In 72 patients, APOE4 was detected in 15 (21%). These investigators found that age and clinical and CT grade were associated with outcome in univariate analysis, as was the presence of APOE4. In multiple logistic regression analysis, the association with APOE4 persisted (OR, 11.3; 95% CI, 2.2 to 57.0; P = .003), although the gain in discrimination was small. Other molecular markers have also been studied, and it is anticipated that in the future, this aspect of SAH will be intensively expanded.⁴⁷

Environmental Factors

Pobereskin found smoking to be positively associated with survival after aneurysmal SAH.⁷⁶

Rebleeding

Rebleeding is strongly correlated with mortality.³²^–³⁴ The rate of rebleeding is highest during the first 24 hours,³²^–³⁴ ⁷⁷ as indicated in Figure 360-3, and may be particularly high during the first 6 hours.⁷⁸ The probability of rebleeding on a daily basis is higher than 4% on the first day, decreases in subsequent days to 1% to 2%, and exhibits a slow decline extending out to 6 months. Factors related to rebleeding are discussed later.

FIGURE 360-3 Acute rebleeding (measured in days) after aneurysm rupture: probability of rebleeding per day after initial subarachnoid hemorrhage (SAH).

(Modified from Kassell NF, Torner JC. Aneurysmal rebleeding: a preliminary report from the Cooperative Aneurysm Study. Neurosurgery. 1983;13:479-481.)

Gender

The influence of gender on outcome after aneurysmal SAH is unclear. Most studies, including population-based analyses, have not identified any difference in mortality in men versus women ⁷⁰ but did note a difference in mortality in premenopausal versus postmenopausal women.⁷⁹

Age

Age has been associated with outcome in conservatively treated patients in some studies. For example, Lagers and colleagues found by both univariate and multivariate analysis that age was correlated with mortality in a population of almost 300 patients.⁷³

Hypertension

The influence of systemic hypertension on outcome after SAH is unclear. This may be related to the elevation in blood pressure after SAH that may be observed in nonhypertensive individuals.

Factors Associated with Rebleeding

A variety of aneurysm and patient factors have been found to be associated with rebleeding in the early phase (hospitalization to 6 months). For example, Hunt-Hess clinical grade on admission (OR, 1.92 per grade; 95% CI, 1.33 to 2.75; P < .001) and maximum aneurysm diameter (OR, 1.07/mm; 95% CI, 1.01 to 1.13; P = .005) were independent predictors of rebleeding.⁸⁰ Other factors associated with rebleeding have been noted to differ, depending on aneurysm location (see Table 360-4). For example, the risk of rebleeding from anterior communicating aneurysms is increased by the following factors: gender (females), aneurysms that point superiorly and have a wide neck, history of coma, systemic hypertension, and elderly age. The associated risk factors for bleeding from posterior communicating aneurysms are different and include age, larger aneurysms, the presence of clot, and vasospasm. More recently, configuration of the aneurysm sac and intra-aneurysm blood flow dynamics as determined by microanalysis have been implicated in rebleeding.⁸¹^–⁸³ Finally, recent studies suggest that molecular and genetics factors may be influencing rebleeding rates.^84,⁸⁵

Late Follow-up: after Six Months

The cooperative aneurysm trial in 1966,⁶⁵^–⁶⁸ as well as the earlier prescient aneurysm trial at Atkinson Morley’s Hospital in Wimbledon, England, under the direction of McKissock and Richardson,^32,^33,^{62–64,86–88} relegated in a random fashion a large number of patients to bed rest. These individuals were then subsequently observed over the course of many years, which allowed the long-term natural history of conservatively treated patients to be defined. Before analyzing these data, the long-term outcome, as measured in years, was thought to be benign,^65,⁸⁹ with the development of “healed” aneurysms and no or minimal risk of rehemorrhage.

Late Rebleeding

Long-term studies have revealed that aneurysms do not “heal.” Instead, long-term follow-up has documented a persistent yearly rebleeding rate of approximately 3% and persistence of this rate well into the second decade of follow-up.^71,⁹⁰ As illustrated in Figure 360-4, the average rebleeding rate over the initial 15 years of observation was 2.74% per year. The rate of rebleeding during the acute period as measured in days is in contrast to the rate of rebleeding as measured in years in Figure 360-5.

FIGURE 360-4 Long-term (6 months after the initial subarachnoid hemorrhage [SAH]) rebleeding rate. The data were derived from 167 patients with a single anterior communicating artery aneurysm who were initially treated by conservative management. The dashed line indicates the average yearly rebleeding rate of 2.74%.

FIGURE 360-5 Relationship between elapsed time and chance of rebleeding from posterior and anterior communicating artery aneurysms. The rate of rebleeding during the acute period measured in days (left) is contrasted with the long-term course measured in years (right).

(Modified from Winn HR, Richardson AE, Jane JA. The long-term prognosis in untreated cerebral aneurysms: I. The incidence of late hemorrhage in cerebral aneurysm: a 10-year evaluation of 364 patients. Ann Neurol. 1977;1:358-370.)

Late Mortality

The overall mortality associated with a late hemorrhage approximated 60%. The mortality rate of 60% is similar to that observed during the acute period (0 to 6 months) when the prehospital deaths are included. It is interesting that 18% of the patient who rebled late died before they could be hospitalized. Over the course of decades of follow-up, the majority of deaths were related to fatal rebleeding, which occurred at a yearly rate of 2% to 3%. Even when late SAH deaths were excluded, these patients had a higher mortality rate than age-matched patients did (Fig. 360-6). The primary cause of non–SAH-associated deaths was cardiovascular disease.

FIGURE 360-6 Long-term outcome in 364 conservatively managed patients with a single anterior or posterior communicating artery aneurysm: observed (in red) versus expected survival. Late deaths from rebleeding were excluded in the former group. Expected survival was based on survival data for a similar population matched for age and gender.

(Modified from Winn HR, Richardson AE, O’Brien W, et al. The long-term prognosis in untreated cerebral aneurysms: II. Late morbidity and mortality. Ann Neurol. 1978;4:418-426.)