Pathogenesis, Natural History, and Treatment of Unruptured Intracranial Aneurysms

SYMPOSIUM ON CEREBROVASCULAR DISEASES UNRUPTURED INTRACRANIAL ANEURYSMS

Pathogenesis, Natural History, and Treatment of Unruptured Intracranial Aneurysms DAVID O. WIEBERS, MD; DAVID G. PIEPGRAS, MD; FREDRIC B. MEYER, MD; DAVID F. KALLMES, MD; IRENE MEISSNER, MD; JOHN L. D. ATKINSON, MD; MICHAEL J. LINK, MD; AND ROBERT D. BROWN, JR, MD, MPH Unruptured intracranial aneurysms (UIAs) are a major public health issue. These lesions have become increasingly recognized in recent years with the advent of advanced cerebral imaging techniques. Epidemiological evidence from multiple sources suggests that most intracranial aneurysms do not rupture. Therefore, it is desirable to identify which UIAs are at greatest risk of rupture when considering which to repair. It is important to compare size-, site-, and group-specific natural history rates with size-, site-, and age-specific morbidity and mortality associated with UIA repair because increased natural history risk often is associated with increased risk of aneurysm repair. Patient age is crucial in decision making because of its major effect on operative morbidity and mortality; however, it does not substantially affect natural history. The effect of age is most notable in patients about 50 years of age and older for open surgery and about 70 years of age and older for endovascular procedures. In general, rupture risk is lowest for patients in asymptomatic group 1 (no history of subarachnoid hemorrhage) with UIAs less than 7 mm in diameter in the anterior circulation. Surgical morbidity and mortality are most favorable for asymptomatic patients younger than 50 years who have UIAs less than 24 mm in diameter in the anterior circulation and no history of ischemic cerebrovascular disease. Endovascular morbidity and mortality may be less age dependent, and this could favor endovascular procedures, particularly in patients aged 50 to 70 years. An important issue is determining immediate vs long-term risk regarding treatment effectiveness and durability. This issue emphasizes the importance of long-term follow-up in patients after surgical and endovascular procedures.

Mayo Clin Proc. 2004;79(12):1572-1583 AVM = arteriovenous malformation; CTA = computed tomographic angiography; ISUIA = International Study of Unruptured Intracranial Aneurysms; MRA = magnetic resonance angiography; SAH = subarachnoid hemorrhage; UIA = unruptured intracranial aneurysm

U

nruptured intracranial aneurysms (UIAs) are a major public health issue. Several autopsy studies have shown a wide range of overall frequency (0.2%-9.9%) for UIAs in the general population.1-6 More recent prospective angiographic and autopsy studies indicate an overall frequency of approximately 2% to 4%,7 implying that UIAs will affect at least 6 million people in the United States at some point during their lives. The mean age of the US population is increasing, and intracranial aneurysms appear From the Department of Neurology (D.O.W., I.M., R.D.B.), Department of Neurologic Surgery (D.G.P., F.B.M., J.L.D.A., M.J.L.), and Division of Neuroradiology (D.F.K.), Mayo Clinic College of Medicine, Rochester, Minn. Individual reprints of this article are not available. The entire Symposium on Cerebrovascular Diseases will be available for purchase as a bound booklet from the Proceedings Editorial Office at a later date. © 2004 Mayo Foundation for Medical Education and Research

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to develop with increasing age.8 The incidence of subarachnoid hemorrhage (SAH) from intracranial aneurysms also increases progressively with age.9 Intracranial aneurysms are commonly undetected until spontaneous rupture causes SAH, intracerebral hemorrhage, or both. However, sometimes aneurysms are diagnosed before rupture because of clinical features unrelated to intracranial hemorrhage. Also, UIAs are discovered while examining patients with SAH from a different aneurysm. The diagnosis may be fortuitous and is often the result of performing computed tomography, computed tomographic angiography (CTA), magnetic resonance imaging, or magnetic resonance angiography (MRA) for unrelated symptoms. In recent years, widespread use of these imaging methods has notably increased the number of aneurysms discovered incidentally, making treatment increasingly relevant. Subarachnoid hemorrhage from ruptured intracranial aneurysms affects an estimated 22,000 patients per year in the United States, and despite significant declines in the overall incidence of stroke during the past 50 years,10,11 the incidence of SAH has not declined.12,13 PATHOGENESIS Approximately 80% to 90% of all intracranial aneurysms are classified as saccular or berry aneurysms, which normally appear as small, rounded, berrylike dilatations. Other shapes (sessile, pedunculated, multilobed) also are seen. Multiple aneurysms occur in 20% to 25% of patients with saccular aneurysms, and approximately 20% of patients with saccular aneurysms have a family history of SAH or intracranial aneurysms.14 Various other pathological entities have been associated with intracranial aneurysms including arteriovenous malformations (AVMs),15-19 polycystic kidney disease,20-22 coarctation of the aorta,23,24 fibromuscular dysplasia,25-28 Marfan syndrome,29 moyamoya disease,30-34 Ehlers-Danlos syndrome,35,36 pseudoxanthoma elasticum,37 and pituitary gland tumors.5 The underlying pathophysiology leading to the development of intracranial aneurysms has long been a subject of controversy. Eppinger38 formally introduced the medial defect theory; later, this theory was expanded by Forbus,39 who opined that aneurysms were acquired lesions resulting

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from degeneration of the elastic membrane because of its continued overstretching, combined with an underlying congenital defect in the muscularis portion of the arterial wall. Noting the relative ubiquity of medial defects in the general population, Glynn40 proposed that the most important factor in producing saccular aneurysms was degeneration of the internal elastic lamina, possibly caused by or otherwise related to atherosclerosis. He suggested that both congenital medial defects and acquired internal elastic lamina defects had to be present before cerebral aneurysms formed. After finding that the frequency of medial defects increased with patient age, Stehbens3 suggested these defects were not congenital and noted that the distribution of these defects in nature was inconsistent with the frequency of distribution of berry aneurysms in humans and other animals. Stehbens further reasoned that medial defects were involved fortuitously; he stated that thinning of the arterial wall occurred early and was associated with degeneration of cells in the elastica and of muscle cells in the intracellular matrix. Also, the increased incidence rates of aneurysmal SAH with increasing age and other clinical observations suggest that intracranial saccular aneurysms are not congenital lesions.8,9 However, this does not preclude a congenital predisposition. Various environmental factors have been implicated on intuitive and experimental grounds as playing an important role in the development of intracranial aneurysms. Many of these environmental factors relate to increased hemodynamic stress and fluid dynamic changes associated with conditions such as systemic hypertension, focal increases in blood flow such as those from contralateral carotid artery occlusion, and atherosclerosis.41-45 However, other clinical studies have failed to show a correlation between hypertension and aneurysmal SAH or the discovery of UIAs.8,9,46,47 Other structural arterial defects have been suggested, primarily on the basis of associated diseases such as Marfan syndrome, pseudoxanthoma elasticum, and Ehlers-Danlos syndrome. GROWTH AND RUPTURE OF ANEURYSMS Much controversy exists about the mechanisms involved with the growth and rupture of intracranial aneurysms. An understanding of such mechanisms is necessary to optimize our knowledge of the clinical behavior of these lesions and to optimize treatment of patients with UIAs. Because of the risk associated with arteriographic studies over the years, relatively little information regarding serial angiography of UIAs is available.48-51 Existing data seem to indicate wide variability in the growth rate of individual aneurysms. Angiographic and clinical evidence seems to suggest that, whereas some aneurysms may inMayo Clin Proc.

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crease in size over several years, others may enlarge considerably in hours to weeks, may decrease in size, or may spontaneously obliterate.48-50 A large percentage of UIAs appear to remain unchanged in size over time, particularly smaller UIAs in patients with no history of prior SAH from a different aneurysm. The increasing quality of noninvasive techniques including CTA and MRA provides further opportunities to learn more about the growth of intracranial aneurysms.52 Several experimental in vitro studies and in vivo clinical observations have implicated intramural hemodynamic factors and, to a lesser extent, extramural physical factors to explain the growth of intracranial aneurysms. Among intrinsic factors, hemodynamic stresses and pulsatile flow patterns have been implicated frequently in aneurysmal growth.39,53,54 Forbus39 and others have shown experimentally that hydrostatic pressure is greater at the apexes of arterial bifurcations than at other angles of the bifurcation or other arterial locations and that this hydrostatic pressure increases with increasing angles of bifurcation and with increasing blood pressure and blood flow. Many investigators have believed that the dissipation of energy at the apex of a bifurcation plays a role in the origin and growth of aneurysms because this is where aneurysms often occur in the arterial tree. Some clinical evidence that pulsatile flow is a factor in the rupture of aneurysms can be derived from Jain’s study53 of 18 instances of rupture when more than 1 aneurysm was located along the same artery. In these cases, the proximal aneurysm ruptured in 12 patients and thrombosed in 6 other patients in whom the distal aneurysm ruptured. Others have emphasized the importance of turbulence in relation to growth of aneurysms. Foreman and Hutchison55 showed that normal blood flow through stenotic arteries induced peaks of vibration that coincided with the natural resonant frequencies of the vessel walls. Musical highpitched bruits have been recorded from intracranial aneurysms during surgery. At certain resonant frequencies, relatively low forces can produce higher strain than usual. Ferguson56,57 suggested that vibrations produced by turbulence occurring at the resonant frequency of the arterial wall may result in structural fatigue, which in turn could lead to weakening of the wall of an aneurysm, with subsequent enlargement or rupture. Other potential mechanisms associated with these bruits include aneurysmal oscillation, Helmholtz resonation, or hydrodynamic whistle.58,59 Scott et al60 found experimentally that distensibility curves of cerebral aneurysms changed abruptly after aneurysms were subjected 3 times to a pressure of 200 mm Hg, and the arteries became brittle. Because the walls of large aneurysms are usually thicker, it has been reasoned that these aneurysms are less likely to rupture. This has been

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countered by more recent clinical evidence showing that larger aneurysms are more likely to rupture,8,14,47,61,62 making less clear the importance of aneurysm wall elasticity for determining future rupture. The potential importance of hemodynamic stresses on the origin and growth of aneurysms is emphasized in circumstances in which intracranial aneurysms and AVMs coexist. In this situation, aneurysms tend to be located on the arteries feeding the AVM, and higher rates of blood flow through the AVM have been correlated with enlargement of the associated aneurysm.63 However, other data involving unruptured AVMs and aneurysms17-19 showed aneurysms occurring in similar percentages among patients with small, medium, and large AVMs; in similar percentages among patients with high-flow, high-shunt, low-flow, and low-shunt AVMs; and in similar percentages among patients with small, medium, and large AVMs. These data suggest that the mechanism by which AVMs predispose to aneurysmal formation within AVM-feeding systems is not based simply on the high shunt or high blood flow in these systems. Aneurysm growth also may be affected by certain extrinsic factors in the aneurysmal environment. Supporting evidence is limited and anecdotal, such as the case report by Scanarini et al64 concerning a patient who had enlargement of a middle cerebral artery aneurysm after removal of part of an adjacent temporal lobe associated with evacuation of an intracerebral hematoma. It is possible that creating a space around the aneurysm via temporal lobectomy contributes directly to the growth of an aneurysm in such patients. Also, it has been postulated that some aneurysmal locations (eg, ophthalmic and cavernous segment internal carotid artery) are more conducive to the development of giant aneurysms because of some protection afforded against rupture by the anterior clinoid process and dura of the cavernous sinus.43 In recent years, some investigators have focused more on the perianeurysmal environment as a predictor of aneurysmal natural history.65-67 Specifically, various elements bounding the subarachnoid space have been implicated including bone, brain, and dura, as well as elements traversing the subarachnoid space including arachnoid villae, cranial nerves, and blood vessels; researchers have observed that the number and nature of the structures that an aneurysm encounters depend on the location of the aneurysm.67 Compact constraints established between an aneurysm and its environment could affect the aneurysm either positively or negatively, offering either protection against rupture or added propensity to rupture.67 For example, aneurysms in the posterior communicating artery, for various reasons, appear to relate to the external perianeurysmal environment and increase the likelihood of rupture. 1574

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Computational fluid dynamics, a scientific and engineering tool, is a recent development that has been proposed as a means of evaluating individual aneurysmal circumstances that could potentially add to predicting the propensity for future rupture.68,69 This mathematical modeling technique offers the potential to investigate and evaluate numerous hemodynamic factors that may lead to aneurysm formation, enlargement, thrombosis, and rupture including shear wall stress, pressure and mural stress, impingement force, flow rate, and residence time. However, additional research will be required to assess the relative importance of these factors and how they may interact with and relate to other factors such as vessel geometry.68,69 A postmortem study,70 in which patients died within 3 weeks after experiencing aneurysmal SAH, has shown that a new protective layer with fibrin as its main component is formed soon after a rupture. This newly formed protective layer is relatively weak in the first 3 weeks, during which time the danger of recurrent bleeding is very high. After 3 weeks, the new wall is reinforced and thickened by capillary proliferation and by resorption of recurrent minor bleeding from these capillaries within the new wall. However, capillary proliferation may lead to the formation of new potential points of rupture. Factors such as these may account for substantial differences in the potential for growth and rupture between previously ruptured and unruptured aneurysms. NATURAL HISTORY STUDIES Clinical data concerning the natural history of UIAs are best considered separately for patients with UIAs and without prior SAH and patients with UIAs and prior SAH from a different aneurysm. PATIENTS WITH UIAS AND WITHOUT PRIOR SAH (GROUP 1) As part of the Cooperative Study of Intracranial Aneurysms and Subarachnoid Hemorrhage, Locksley71 described 34 patients with unoperated UIAs, of whom only 19 had long-term follow-up (≥5 years or until death). Among these 19 patients, 8 died of spontaneous SAH, and 1 died after lumbar puncture. All 8 patients with ruptures had aneurysms that were 7 to 11 mm in diameter or larger (precise sizes were unavailable). No aneurysm less than 7 mm in diameter ruptured, and it was not indicated whether any aneurysm less than 10 mm in diameter ruptured. Zacks et al72 reported on 10 patients with fortuitously discovered untreated UIAs who were followed up for 7 weeks to 71/2 years. None of the patients had intracranial hemorrhages during follow-up, but only 2 were followed up for 5 years or more after diagnosis or until death. None of the aneurysms exceeded 10 mm in diameter.

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UNRUPTURED INTRACRANIAL ANEURYSMS

Wiebers et al47 studied 65 patients with 81 UIAs and reported a mean follow-up of approximately 8 years. All patients were followed up for at least 5 years or until death. A multivariate discriminant analysis assessed the relative impact of several variables upon aneurysmal rupture. The only variable of unquestionable significance was aneurysmal size. None of 44 aneurysms less than 1 cm in diameter ruptured, whereas 8 of 29 aneurysms 1 cm or greater in diameter ruptured eventually. The presence of multiple aneurysmal lobes and aneurysmal symptoms other than rupture also showed a positive correlation with eventual rupture with univariate analysis. However, multivariate analysis showed that the increased risk of rupture for multilobed aneurysms and aneurysms producing symptoms other than rupture could be attributed solely to aneurysmal size. This and other studies71 have documented that aneurysms 7 mm or smaller in diameter seldom cause symptoms unrelated to rupture and that many aneurysms larger than 7 mm in diameter, particularly those between 8 and 20 mm, also do not cause such symptoms. Wiebers et al8 subsequently extended their experience by monitoring a larger group of patients with unoperated UIAs. Altogether, 15 of 130 patients (with 161 aneurysms) had intracranial hemorrhage over a mean follow-up interval of 8.3 years. Among 102 aneurysms smaller than 1 cm in diameter, none ruptured during the follow-up period, whereas 15 of 51 aneurysms 1 cm or larger in diameter ruptured eventually. Five of the 15 ruptures occurred within 3 months of the diagnosis of intracranial aneurysm, and 14 of the 15 ruptures were fatal. As with the previous study, the only single variable of unquestionable significance for predicting aneurysmal rupture was aneurysmal size (P<.0001). However, when combinations of variables were analyzed, the interaction of aneurysmal size and patient age was even more significant than aneurysmal size alone (P<.00001). A considerably worse prognosis was noted when the age of the patient (in years) multiplied by the greatest diameters of the aneurysm (in mm) exceeded 1000. In a subsequent study by Yasui et al,73 234 patients with or without prior SAH were evaluated for 6.2 years; 34 patients (14.5%) experienced subsequent SAH with a reported average annual rupture rate of 2.3%. It was unclear what rate could be applied to patients with or without prior SAH. In a separate study, Yasui et al74 evaluated aneurysmal size in 25 patients with or without prior SAH and rupture of a previously unruptured aneurysm. Twenty-two of the newly ruptured aneurysms were less than 9 mm in diameter at initial diagnosis, and 16 were less than 5 mm in diameter. Aneurysmal size increased in 19 of 20 patients who were reassessed angiographically after rupture. Again, it was unclear which patients with subsequent SAH had or did not have a history of SAH before identification of their UIA. Mayo Clin Proc.

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The International Study of Unruptured Intracranial Aneurysms (ISUIA) represents a multicenter collaborative effort organized in 1990 to study the natural history of UIAs and to characterize and quantify the morbidity and mortality associated with UIA repair. A report from this study group in 199814 included a natural history component based on retrospectively identified patients using predefined criteria for patient entry and aneurysmal rupture across multiple centers. The study design involved central remeasurement of all aneurysms with hard-copy arteriographic films, a defined system for magnification correction, and a published methodology for in-depth detection, review, and adjudication of detailed data regarding outcome events. This study also included sufficient numbers of patients to allow secondary subgroup analysis according to aneurysmal size, aneurysmal location, and history of SAH from a different aneurysm. The study14 monitored 727 patients with UIAs and no history of SAH from another aneurysm for a mean of 7.5 years. Among patients with UIAs less than 10 mm in diameter, the subsequent rupture rate was less than one tenth of 1% per year. The rupture rate for patients with UIAs 10 mm or greater in diameter was approximately 1% per year, including a rate of approximately 6% in the first year among patients with giant (≥25 mm) UIAs. Aneurysmal location also predicted future rupture (aneurysms in the posterior communicating, vertebral basilar, posterior cerebral, and basilar tip arterial locations were more likely to rupture). However, aneurysmal size was the best predictor of future rupture. Other patient demographic characteristics, aneurysmal characteristics, aneurysmal symptoms other than rupture, behavioral factors, and associated medical conditions did not independently predict future rupture. Even more recently, ISUIA investigators have reported prospective natural history data pertaining to UIAs on the basis of a prospective cohort involving 1692 patients with 2686 UIAs, including 1077 patients in group 1 and 615 in group 2.62 Before this study, all natural history studies had been based on retrospective patient identification, which, by the very nature of such a cohort, inevitably raises some question about the potential for selection bias. Among the prospective cohort, the diagnosis of UIA was made between 1991 and 1997 and was based on centrally reviewed hard-copy arteriographic studies. The mean age of the cohort was 55 years, approximately three fourths of patients were female, and the mean follow-up interval was 4.1 years for a total of 6544 patient-years of follow-up. As with the retrospective ISUIA cohort, larger aneurysmal size predicted greater risk of rupture. Also, aneurysmal location was important for predicting future UIA rupture, with greater risk associated with UIAs in the posterior circulation and the posterior communicating artery and lesser risk

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associated with UIAs in the carotid cavernous artery. Although rupture rates and the predictors of rupture followed the same patterns as with the retrospective ISUIA cohort, the rupture rates for the prospective cohort were higher than those of the retrospective cohort for UIAs 7 mm or greater in diameter. Running averages for predetermined 3mm successive size categories, used for the ISUIA retrospective cohort, revealed optimal cut points at diameters less than 7 mm, 7 to 12 mm, 13 to 24 mm, and 25 mm or larger. Rupture rates at 3 sets of locations were statistically different and therefore were used in models for predicting rupture. A comparison of patients without (group 1) and with (group 2) a history of SAH revealed significantly higher rupture rates among group 2 patients with UIAs less than 7 mm in diameter (P<.0001). Of note, approximately half of the group 2 patients had UIAs less than 7 mm in diameter. Otherwise, rupture rates for patients in group 1 and group 2 did not differ. Five-year cumulative hemorrhage rates by aneurysmal site (parent artery), size (4 size categories), and patient group (for aneurysms <7 mm) are shown in Table 1.62 PATIENTS WITH UIAS AND PRIOR SAH (GROUP 2) Winn et al75 evaluated 182 patients with multiple aneurysms and SAH during a mean follow-up period of 7.7 years. Among the cohort, 132 patients were treated with bed rest and 50 with surgery directed at the unruptured aneurysm. In the bed-rest group, 21 patients (16%) had a late hemorrhage, which investigators concluded was due to rerupture of the original aneurysm. Among the surgically treated group, patients underwent wrapping or clipping of the aneurysm or ligation of the carotid artery. Of the 50 surgically treated patients, 10 (20%) experienced subsequent intracranial hemorrhage. Three patients were believed to have bled from a previously intact aneurysm. No correlation was found between the size of the secondlargest aneurysm and the propensity for rupture. However, for the entire patient group, those experiencing late rebleeding included a significantly greater proportion of patients with aneurysms 10 mm or larger in diameter. Heiskanen76 monitored a similar group of 61 patients who had SAH, at least 2 intracranial aneurysms, and clipping of the ruptured aneurysm. During a 10-year follow-up, 7 patients were believed to have bled from a previously unruptured aneurysm, and 3 patients had fatal bleeding more than 10 years after the first SAH. No aneurysmal sizes were noted. In another series, Juvela et al61 studied 142 patients with 181 UIAs. Patients were monitored until death, until SAH, or for 10 years or more for a mean of 13.9 years. Most (131) of these 142 patients had prior SAH from a separate aneurysm that was repaired. The authors reported an annual 1576

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rupture rate of UIAs of 1.4% for the entire group. Aneurysmal size was the only variable studied that predicted future rupture; however, the strength of this predictive value was marginal for the entire population (P=.036) and was not statistically significant for the 131 patients with prior SAH. Subsequent follow-up of the 57 remaining patients from this cohort yielded similar results.77 In the report by the ISUIA investigators involving the retrospective natural history cohort,14 722 patients were identified with a history of SAH, and these patients were followed up for a mean of 7.5 years. The rupture rates for group 2 patients with UIAs less than 10 mm in diameter were 11 times higher than the rates for group 1 patients without prior SAH and the same size UIAs. The only clear predictor of future rupture among these patients was location (UIAs at the basilar tip site); size alone did not appear to predict future rupture in this cohort. In the more recent report from ISUIA involving the prospective natural history component,62 as discussed previously, the aneurysmal rupture rates for group 2 patients were significantly higher than rates for group 1 patients with aneurysms less than 7 mm in diameter; therefore, aneurysmal rupture rates for group 2 patients (Table 1) are shown separately in the various locations only for UIAs less than 7 mm in diameter. The overall pattern and magnitude of rupture rates in the ISUIA prospective natural history series for group 2 patients were virtually identical to those reported for the retrospective series.14 PATHOPHYSIOLOGY OF ANEURYSMAL DEVELOPMENT, GROWTH, AND RUPTURE Over the years, some investigators have called attention to patients with small ruptured aneurysms diagnosed after SAH, inferring that small UIAs, even in group 1, may have substantial rupture rates.78 Others have attempted to extrapolate the natural history of UIAs by considering incidence rates of SAH to infer prevalences of UIAs in the population.79 It is important to recognize that ruptured intracranial aneurysms and UIAs constitute distinctly different clinical entities and need to be considered and managed as such. Findings of ISUIA and other natural history studies reinforce this difference and the fact that the natural history of UIAs cannot be extrapolated from patients with ruptured aneurysms. Much confusion has surrounded this issue by not recognizing the major differences between the following 2 questions: (1) What is the probability of a ruptured aneurysm being a certain size? (2) What is the probability of future rupture of a given-sized aneurysm discovered before rupture? The second question is relevant to the clinical treatment of patients with UIAs. The bottom line is that little is learned about the natural history of

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unruptured aneurysms by referring to characteristics of patients with ruptured aneurysms. This statement strongly applies not only to aneurysmal size but also to location. Available evidence suggests that most aneurysms that will rupture do so at the time they form or soon after and that the critical size for rupture is lower for aneurysms that rupture early. In the study by Wiebers et al,8 the sizes of aneurysms that ruptured ranged from 10 to 40 mm in diameter before rupture, with a mean diameter of 21.3 mm. The authors noted a discrepancy between this observation and the observation that the mean size of ruptured aneurysms as seen arteriographically over the prior 10 years at the Mayo Clinic in Rochester, Minn, was approximately 7.5 mm in diameter. Similar discrepancies have been observed in subsequent retrospective14 and prospective62 studies of the natural history of UIAs. Three possible explanations were suggested for the discrepancy in ruptured aneurysm size.8 First, small aneurysms could so greatly outnumber large aneurysms that a very small percentage of small aneurysms that rupture could still represent a substantial fraction of all aneurysmal ruptures. Whether this explanation can fully account for the discrepancy is doubtful. From the initial observations involving 102 aneurysms smaller than 10 mm in diameter with 824 person-years of follow-up, a ratio was calculated (with >95% confidence) of aneurysm diameters (<10 mm vs >10 mm) that would need to be at least 60:1 to account fully for the discrepancy. However, autopsy and arteriographic data provided previously by Locksley,80 McCormick and Acosta-Rua,4 and others suggest ratios in the range of 5:1 to 6:1. A second possible explanation was a decrease in arteriographic aneurysmal size after rupture caused either by partial collapse of the aneurysmal walls at the time of rupture or by thrombus formation w ithin the aneurys mal sac, which could decrease the arteriographic lumen size without decreasing the overall external size of the aneurysm. Spontaneous decreases in aneurysmal size have been documented, occurring without rupture in isolated cases, but no meaningful data are available on arteriographic appearance of aneurysms immediately before and after rupture. The third and most compelling explanation offered was that the critical size for aneurysmal rupture is smaller for aneurysms that rupture at the time of or soon after formation. On the basis of the previous considerations, other clinical and natural history data, and available data on the pathophysiology of intracranial aneurysms, the following scenario of aneurysmal development and rupture was proposed8: Intracranial saccular aneurysms are not congenital lesions; rather, they develop with increasing age. Most intracranial aneurysms probably develop over a relatively short period, measured in hours, days, or weeks, attaining a Mayo Clin Proc.

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TABLE 1. Five-Year Cumulative Rupture Rates According to UIA Size, Location, and Patient Group, Among Patients in the Unoperated Cohort (N=1692)* Aneurysmal size <7 mm

Aneurysmal location

No. of patients

Cavernous AC/MC/IC Post-P comm

210 1037

0.0 0.0

445

2.5

7-12 mm

13-24 mm

≥25 mm

0.0 1.5

0.0 2.6

3.0 14.5

6.4 40

3.4

14.5

18.4

50

Group 1† Group 2‡

*Values are percentages unless indicated otherwise. AC = anterior communicating or anterior cerebral artery; Cavernous = cavernous carotid artery; IC = internal carotid artery (not cavernous carotid artery); MC = middle cerebral artery; Post-P comm = vertebrobasilar, posterior cerebral arterial system, or the posterior communicating artery; UIA = unruptured intracranial aneurysm. †Patients had no history of subarachnoid hemorrhage. ‡Patients had a history of subarachnoid hemorrhage from a separate aneurysm. Reprinted with permission from Elsevier (Lancet. 2003;362:103-110).62

size allowed by the elasticity limits of the elastic components of the aneurysmal walls. At this point, the aneurysm either ruptures or, if the limits of elasticity are not exceeded and the aneurysm remains intact, the aneurysmal walls undergo a process of compensatory hardening, similar to other vascular structures subjected to arterial blood pressures over time, with the formation of excessive amounts of collagen.81,82 The tensile strength of collagen is several hundred times that of elastic fibers.82 With this added tensile strength, which accumulates over time, the likelihood of rupture decreases unless the size of the aneurysm is fairly large at the time it initially stabilizes. Aneurysms 1 cm or larger at the time of initial stabilization are considerably more likely to undergo subsequent growth and rupture because the stress on the wall increases with the square of the diameter of the aneurysm, according to the law of Laplace. From these considerations, it follows that the critical size for aneurysmal rupture is smaller if rupture occurs at the time of or soon after aneurysm formation, as would appear to be true for the vast majority of small aneurysms that rupture. Chronic hypertension appears to have little or no effect on either the prevalence of intracranial aneurysms or their propensity for subsequent rupture. However, sudden elevations of blood pressure may have a greater influence on aneurysmal rupture and may be difficult to identify, even in studies incorporating prospective follow-up. Of note, these hypotheses have been formulated primarily on the basis of data from patients with UIAs who had no history of prior SAH and likely cannot be applied as clearly to patients with UIA with prior SAH from a different aneurysm. The same underlying pathophysiological mechanism(s) that caused an initial aneurysmal rupture

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(eg, tissue fragility) likely puts many of these patients at higher risk of subsequent rupture of a second aneurysm. Aneurysmal location is another parameter that has further reinforced the inability to predict the natural history of UIAs by assessing characteristics of series of patients with ruptured aneurysms. This is particularly apparent in the anterior communicating artery where, in ruptured aneurysm series, 30% to 35% of ruptured aneurysms commonly arise. In contrast, among unruptured aneurysm series, the percentage of such aneurysms is much lower. In ISUIA,14,62 only 10% to 15% of more than 5500 patients had aneurysms in the anterior communicating artery, implying that these aneurysms are particularly prone to develop and rupture early and do not tend to stabilize or be included in studies involving patients with UIAs. In sharp contrast to the natural history that would be predicted on the basis of ruptured aneurysm series, patients with UIAs in the anterior communicating artery are at substantially less risk of future aneurysmal rupture than are patients with aneurysms in many other locations, including the posterior circulation and the posterior communicating artery.62 TREATMENT CONSIDERATIONS Patient treatment decisions involve consideration of not only the natural history of UIAs but also the morbidity and mortality rates associated with treatment including direct surgery and endovascular methods. DIRECT SURGICAL TREATMENT Historically, most available data regarding direct surgical treatment of UIAs were derived from case series involving 1 or more neurosurgeons who evaluated and reported their own outcomes. Overall morbidity and mortality rates ranged from 0% to 7% for death and 4% to 15.3% for complications.83-91 In 2 subsequent meta-analyses,92,93 somewhat discrepant results were reported. The first of these included 733 patients and reported a mortality rate of 1% and a morbidity rate of 4%.92 The second involved 2460 patients and reported a 2.6% mortality rate and a 10.9% permanent morbidity rate.93 Adding to the challenge of performing and interpreting both of these meta-analyses was the lack of uniformity for defining good vs poor outcomes or even mortality rates, which were variably defined at 30 days, 3 to 6 months, or 1 year after surgery. None of the individual studies contained enough patients to warrant conclusive judgments about predictors of outcome. Surgical morbidity and mortality have been assessed more recently by ISUIA.14,62 Study methods included prospective assessment of systematic cognitive status and other forms of neurologic disability before and after UIA repair across multiple centers with a team-evaluation ap1578

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proach. Patients were entered prospectively between the years 1991 and 1997, and end points were centrally adjudicated using a uniform set of predefined criteria for each outcome. In the phase 1 ISUIA report,14 798 patients without prior SAH were assessed. Surgical mortality rates were 2.3% at 30 days and 3.8% at 1 year. Among patients with UIA and prior SAH from a treated aneurysm, mortality rates were 0% at 30 days and 1% at 1 year. The overall rate of surgical morbidity and mortality was 17.5% in group 1 and 13.6% in group 2 at 30 days and was 15.7% and 13.1%, respectively, at 1 year. Patient age was recognized as an important risk factor influencing surgical outcome. A more recent report62 from ISUIA included 1917 patients who prospectively underwent surgical treatment of UIAs from phases 1 and 2 of the study. In this report, overall surgical morbidity and mortality rates at 1 year were reported at 12.6% for group 1 and 10.1% for group 2. The improved rates observed in phase 2 vs phase 1 of ISUIA were attributed primarily to younger patients undergoing surgery in phase 2. Patient age was a strong predictor of outcome (Figure 1), with risk increasing substantially at about age 50 years and older and escalating considerably beyond ages 60 and 70 years.62 Other variables predicting poor surgical outcomes in multivariate analyses were larger aneursymal size, aneurysms in the posterior circulation, history of prior ischemic cerebrovascular disease, and aneurysmal symptoms other than rupture. Figure 2 shows 1-year surgical morbidity and mortality rates according to the interactions of patient age and aneurysmal size and location.62 ENDOVASCULAR TREATMENT Endovascular treatment for patients with UIAs is a more recent therapeutic option than direct surgery; consequently, fewer data exist about outcomes of endovascular repair of UIAs. In a retrospective cohort study involving patients with UIAs treated between 1994 and 1997 at 60 university hospitals, Johnston et al94 compared treatment results among 255 patients treated with endovascular coils and 2357 treated with direct surgery. Adverse outcomes were defined as in-hospital deaths or discharges to nursing homes or rehabilitation hospitals and were reported in 10.6% of endovascular patients and 18.5% of surgical patients. In a separate retrospective assessment using the University of California at San Francisco (UCSF) Hospital discharge database,95 118 surgically treated patients with UIAs were compared with 98 patients treated with endovascular procedures. Patients were judged retrospectively by the authors to have been candidates for either procedure. Of the surgically treated group, 25% had poor outcomes compared with 8% of the endovascularly treated group. Among the surgically treated cohort, 34% displayed persis-

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tent or new symptoms at an average of 3.9 years after treatment compared with 8% of patients who received endovascular treatment. One further retrospective analysis based on patients treated in the state of California between 1990 and 1998 defined adverse events as in-hospital death or discharge to a nursing home or rehabilitation hospital at any point throughout the treatment course. Such events were reported in 25% of the surgical group compared with 10% of the endovascular group.96 Brilstra et al97 undertook a meta-analysis involving 1383 patients treated with endovascular coiling for ruptured aneurysms or UIAs and reported a low permanent complication rate (3.7%) along with a low rate of complete obliteration (54%). The ISUIA investigators recently reported outcomes involving 451 prospectively identified patients with UIAs treated with endovascular procedures.62 Overall morbidity and mortality associated with endovascular repair was 9.1% at 30 days and 9.5% at 1 year. The endovascular treatment cohort was found to be a higher-risk group than those receiving direct surgery in ISUIA because of increased patient age, increased aneurysmal size, and more aneurysms in the posterior circulation treated with endovascular procedures. A multivariate analysis revealed that increased aneurysmal size and aneurysms in the posterior circulation predicted increased risk for patients undergoing endovascular procedures. Importantly, patient age was not a significant predictor of outcome in contrast to patients treated with open surgery. Figure 3 shows 1-year endovascular morbidity and mortality rates according to the interactions of patient age and aneurysmal size and location. From a statistical perspective, the endovascular cohort analyses were associated generally with wider confidence intervals than the direct surgery cohort analyses because of the smaller sample size of the endovascular group. Another treatment consideration involves the performance of carotid endarterectomy in patients with unruptured aneurysms. At least 139 cases involving endarterectomy in patients with intracranial aneurysms have been reported.98-106 Among 135 patients without reported prior SAH, 5 had subsequent aneurysmal rupture at intervals ranging from 2 days to 10 months after endarterectomy. Among 4 patients with prior SAH, 3 had ruptures after carotid endarterectomy. One further treatment consideration relates to patients with unruptured aneurysms and intracranial AVMs. The coincidence of these lesions is a more common occurrence than recognized previously.19 Among 4060 patients entered prospectively into ISUIA, 72 (2%) had coexistent intracranial AVMs.62 Close inspection of arteriograms of 91 patients with unruptured intracranial AVMs revealed that patients had 20 coexisting UIAs.17 The risk of SAH in this Mayo Clin Proc.

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Patients (%)

UNRUPTURED INTRACRANIAL ANEURYSMS

45 40 35 30 25 20 15 10 5 0 <40

40-49

50-59

60-69

≥70

Age of patients (y)

FIGURE 1. Poor surgical outcomes (death, Rankin score of 3-5, or impaired cognitive status) at 1 year by patient age. Error bars represent 95% confidence intervals. Reprinted with permission from Elsevier (Lancet. 2003;362:103-110).62

group was approximately double that among patients with unruptured AVMs alone. Virtually all the aneurysms occurred within the feeding systems of the AVMs, and the extra risk conferred by the presence of aneurysms did not clearly relate to aneurysmal size. MANAGEMENT SUGGESTIONS Epidemiological evidence from multiple vantage points suggests that most intracranial aneurysms do not rupture. Therefore, it is desirable to identify which unruptured aneurysms are at greatest risk of subsequent rupture when considering which to repair. Optimal treatment of patients with UIAs also involves predicting which patients will have the greatest likelihood of success and the lowest complication rates from repairing UIAs and reconciling these data with natural history data involving UIAs and with patients’ informed perspective regarding their desire to have the aneurysm treated. After publication of the phase 1 ISUIA data,14 an expert panel convened by the American Heart Association concluded that “in consideration of the apparent low risk of hemorrhage from incidental small (<10 mm) aneurysms in patients without previous SAH, treatment rather than observation cannot be generally advocated.”107 With an evidence-based medicine approach, Brennan and Schwartz108 concluded that conservative treatment was warranted for group 1 patients with UIAs less than 10 mm in diameter and for all patients with UIAs who were younger than 64 years. Johnston et al,109 in an extensive cost-utility analysis regarding UIAs, indicated that “Treatment of small, asymptomatic, unruptured cerebral aneurysms in patients without a history of SAH worsens clinical outcomes, and thus is neither effective nor cost-effective.”

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60

≤12 mm 13-24 mm ≥25 mm

Patients (%)

50 40 30 20 10 0

<50

≥50

Age of patients (y) Anterior circulation aneurysms

<50

≥50

Age of patients (y) Posterior circulation aneurysms

FIGURE 2. Poor surgical outcomes (death, Rankin score of 3-5, or impaired cognitive status) at 1 year by patient age and aneurysmal site and size. Error bars represent 95% confidence intervals. Reprinted with permission from Elsevier (Lancet. 2003;362:103110).62

The newest ISUIA information62 generally supports these recommendations but allows a more individualized, detailed, and sophisticated assessment of the risks of natural history vs the risks of surgical and/or endovascular repair on the basis of much more than aneurysmal size. However, for group 1 patients with aneurysms less than 7 mm in diameter, it is very unlikely that the natural history of these lesions can be improved, particularly in older patients and in those with aneurysms in the anterior circulation. Current data cannot establish that a family history of UIA or SAH increases risk in this group. Of note, available natural history studies, including ISUIA, include very few symptomatic patients with small UIAs, particularly those with acute or changing symptoms, and virtually no patients with observed aneurysmal growth; these rare circumstances may constitute exceptions to the broader principle. For most other patients with UIA, more substantial rupture rates apply according to aneurysmal size and location, and more sophisticated comparisons are now possible that are based on more than aneurysmal size. It is important to compare size-, site-, and group-specific natural history rates with size-, site-, and age-specific morbidity and mortality associated with UIA repair (Table 1; Figures 1-3). Higher natural history risk is often but not always associated with higher treatment morbidity and mortality. A crucial element in decision making is the age of the patient, primarily because age has a major effect on operative morbidity and mortality but relatively little effect on natural history. This effect of age is most notable in patients about 50 years of age and older for open surgery and about 70 years of age and older for endovascular procedures. 1580

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In general, the aneurysmal rupture risk is lowest for asymptomatic group 1 patients with UIAs less than 7 mm in diameter in the anterior circulation. Surgical morbidity and mortality are most favorable for asymptomatic patients younger than 50 years with UIAs in the anterior circulation less than 24 mm in diameter and no history of ischemic cerebrovascular disease. Endovascular morbidity and mortality may be less age dependent and this could favor endovascular procedures, particularly in patients between ages 50 and 70 years. It is also very important to consider the immediate vs long-term risk with regard to treatment effectiveness and durability. This issue reinforces the need for long-term follow-up in patients after open surgery and endovascular procedures to assess not only immediate and short-term complications but also long-term effectiveness. Routine screening for UIAs with noninvasive tests such as computed tomography (CT/CTA) or magnetic resonance imaging (MRI/MRA) in asymptomatic patients would be expected to have a very low yield in the general population because although aneurysms are often prevalent at autopsy, they develop with increasing age. Even among patients with other predisposing medical conditions, such as autosomal dominant polycystic kidney disease, routine screening for UIAs may have a very low yield, particularly in younger patients.21 In patients with autosomal dominant polycystic kidney disease, noninvasive screening is recommended typically in certain subgroups of patients, namely those with a family history of intracranial aneurysm or SAH. Also, in families without clear genetic conditions predisposing to aneurysm or SAH, if 2 or more family members have intracranial aneurysm or SAH, screening of

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UNRUPTURED INTRACRANIAL ANEURYSMS

60

≤12 mm 13-24 mm ≥25 mm

Patients (%)

50 40 30 20 10 0

<50

≥50

Age of patients (y) Anterior circulation aneurysms

≥50

<50

Age of patients (y) Posterior circulation aneurysms

FIGURE 3. Poor endovascular outcomes (death, Rankin score of 3-5, or impaired cognitive status) at 1 year by patient age and aneurysmal site and size. Error bars represent 95% confidence intervals. Reprinted with permission from Elsevier (Lancet. 2003;362:103-110).62

the first-degree relatives with either MRA or CTA is usually considered.110,111 Although screening usually is not performed in families with only 1 member affected by SAH or aneurysm,112 some family members may request screening for reassurance, and in such circumstances, noninvasive screening is performed with either MRA or CTA. Among patients with both UIA and intracranial AVM, the UIA usually will be located within the feeding system of the AVM. These UIAs are likely to be more prone to future growth and rupture than are UIAs in general.21 When intervention is contemplated, repairing the UIA before addressing the AVM is usually recommended, especially in patients with large UIAs, because sudden changes in the hemodynamics of the feeding system may predispose to aneurysmal rupture. Regarding potential candidates for carotid endarterectomy who also have UIAs, the sudden change of hemodynamics in the distal carotid artery system from correcting a pressure-significant stenosis may predispose to enlargement or rupture of a previously unruptured intracranial aneurysm. Even endarterectomy for non–pressure-significant stensosis could cause substantial distal carotid artery system pressure alterations with clamping and unclamping. Alternatively, among patients with severe carotid artery stenosis, clipping of a UIA could increase the risk of perioperative ischemic stroke with decreases in perfusion pressure during anesthesia or other factors relating to increased thrombogenesis. Although data are too sparse to allow definitive conclusions, it appears that carotid endarterectomy should be approached with increased caution in patients with UIAs, particularly in patients with UIAs 7 Mayo Clin Proc.

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mm or larger in diameter in the ipsilateral carotid artery system and in patients with UIAs and a history of SAH from a separate aneurysm. When repair of UIAs is considered, it should be remembered that evidence suggests substantially lower complication rates are associated with institutions and physicians with many patients who have cerebral aneurysms that are treated on an ongoing basis.78,96,113,114 Therefore, finding physicians and institutions with substantial ongoing experience with these procedures is very important. When UIAs are left untreated and monitored, it seems advisable to suggest that patients avoid smoking (and passive smoke), heavy alcohol consumption, stimulant medications and drugs, and excessive straining and Valsalva maneuvers resulting in major sudden increases in blood pressure. Daily physical activities need not be altered. Although there are many other medical reasons to treat chronic hypertension, data from ISUIA and other studies indicate that chronic hypertension may have little or no effect on aneurysmal development or future rupture of UIAs. For those with UIAs who are not treated with coiling, clipping, or other intervention, UIAs generally are monitored annually with MRA or CTA for 2 to 3 years and then every 2 to 5 years thereafter if the UIAs are clinically and radiographically stable. REFERENCES 1. Housepian EM, Pool JL. A systematic analysis of intracranial aneurysms from the autopsy file of the Presbyterian Hospital, 1914 to 1956. J Neuropathol Exp Neurol. 1958;17:409-423. 2. Chason JL, Hindman WM. Berry aneurysms of the circle of Willis: results of a planned autopsy study. Neurology. 1958;8:41-44. 3. Stehbens WE. Aneurysms and anatomical variation of cerebral arteries. Arch Pathol. 1963;75:45-64.

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4. McCormick WF, Acosta-Rua GJ. The size of intracranial saccular aneurysms: an autopsy study. J Neurosurg. 1970;33:422-427. 5. Jakubowski J, Kendall B. Coincidental aneurysms with tumours of pituitary origin. J Neurol Neurosurg Psychiatry. 1978;41:972-979. 6. Cohen MM. Cerebrovascular accidents: a study of two hundred one cases. AMA Arch Pathol. 1955;60:296-307. 7. Rinkel GJ, Djibuti M, Algra A, van Gijn J. Prevalence and risk of rupture of intracranial aneurysms: a systematic review. Stroke. 1998;29:251-256. 8. Wiebers DO, Whisnant JP, Sundt TM Jr, O’Fallon WM. The significance of unruptured intracranial sac cular aneurysms. J Neurosurg. 1987;66: 23-29. 9. Phillips LH II, Whisnant JP, O’Fallon WM, Sundt TM Jr. The unchanging pattern of subarachnoid hemorrhage in a community. Neurology. 1980;30: 1034-1040. 10. Garraway WM, Whisnant JP, Drury I. The continuing decline in the incidence of stroke. Mayo Clin Proc. 1983;58:520-523. 11. Broderick JP, Phillips SJ, Whisnant JP, O’Fallon WM, Bergstralh EJ. Incidence rates of stroke in the eighties: the end of the decline in stroke? Stroke. 1989;20:577-582. 12. Ingall T, Wiebers D. Natural history of subarachnoid hemorrhage. In: Whisnant JP, ed. Stroke: Populations, Cohorts, and Clinical Trials. Oxford, England: Butterworth-Heinemann; 1993:174-186. 13. Brown RD Jr, Wiebers DO. Subarachnoid hemorrhage and unruptured intracranial aneurysms. In: Ginsberg MD, Bogousslavsky J, eds. Cerebrovascular Disease: Pathophysiology, Diagnosis, and Management. Vol 2. Malden, Mass: Blackwell Science; 1998:1502-1531. 14. International Study of Unruptured Intracranial Aneurysms Investigators. Unruptured intracranial aneurysms—risk of rupture and risks of surgical intervention [published correction appears in N Engl J Med. 1999;340:744]. N Engl J Med. 1998;339:1725-1733. 15. Anderson RM, Blackwood W. The association of arteriovenous angioma and saccular aneurysm of the arteries of the brain. J Pathol Bacteriol. 1959;77:101-110. 16. Suzuki J, Onuma T. Intracranial aneurysms associated with arteriovenous malformations. J Neurosurg. 1979;50:742-746. 17. Brown RD Jr, Wiebers DO, Forbes G, et al. The natural history of unruptured intracranial arteriovenous malformations. J Neurosurg. 1988;68:352357. 18. Brown RD, Wiebers DO, Forbes GS. The relationship of unruptured intracranial arteriovenous malformations to intracranial aneurysms [abstract]. Ann Neurol. 1989;26:127. 19. Brown RD Jr, Wiebers DO, Forbes GS. Unruptured intracranial aneurysms and arteriovenous malformations: frequency of intracranial hemorrhage and relationship of lesions. J Neurosurg. 1990;73:859-863. 20. Iglesias CG, Torres VE, Offord KP, Holley KE, Beard CM, Kurland LT. Epidemiology of adult polycystic kidney disease, Olmsted County, Minnesota: 1935-1980. Am J Kidney Dis. 1983;2:630-639. 21. Wiebers DO, Torres VE. Screening for unruptured intracranial aneurysms in autosomal dominant polycystic kidney disease [editorial]. N Engl J Med. 1992;327:953-955. 22. Lozano AM, Leblanc R. Cerebral aneurysms and polycystic kidney disease: a critical review. Can J Neurol Sci. 1992;19:222-227. 23. Reifenstein GH, Levine SA, Gross RE. Coarctation of the aorta: a review of 104 autopsied cases of the “adult type,” 2 years of age or older. Am Heart J. 1947;33:146-168. 24. Connolly HM, Huston J III, Brown RD Jr, Warnes CA, Ammash NM, Tajik AJ. Intracranial aneurysms in patients with coarctation of the aorta: a prospective magnetic resonance angiographic study of 100 patients. Mayo Clin Proc. 2003;78:1491-1499. 25. Palubinskas AJ, Perloff D, Newton TH. Fibromuscular hyperplasia, an arterial dysplasia of increasing clinical importance. Am J Roentgenol Radium Ther Nucl Med. 1966;98:907-913. 26. Wylie EJ, Binkley FM, Palubinskas AJ. Extrarenal fibromuscular hyperplasia. Am J Surg. 1966;112:149-155. 27. Belber CJ, Hoffman RB. The syndrome of intracranial aneurysm associated with fibromuscular hyperplasia of the renal arteries. J Neurosurg. 1968; 28:556-559. 28. Bolander H, Hassler O, Liliequist B, West KA. Cerebral aneurysm in an infant with fibromuscular hyperplasia of the renal arteries: case report. J Neurosurg. 1978;49:756-759. 29. Finney LH, Roberts TS, Anderson RE. Giant intracranial aneurysm associated with Marfan’s syndrome: case report. J Neurosurg. 1976;45:342-347. 30. Pool JL, Wood EH, Maki Y. On the cases with abnormal vascular networks in the cerebral basal region in the United States. In: Kudo T, ed. A Disease With Abnormal Intracranial Vascular Networks: Spontaneous Occlusion of the Circle of Willis. Tokyo, Japan: Igaku-Shoin; 1967:63-69. 31. Yasargil MG, Smith RD. Association of middle cerebral artery anomalies with saccular aneurysms and Moyamoya disease. Surg Neurol. 1976;6:3943.

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