Unruptured Intracranial Aneurysms â€” Risk of Rupture and Risks of Surgical Intervention

Volume 339 Number 24

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The New England

Journal

of

Medicine

© Copyr ight, 1998, by the Massachusetts Medical Society

VOLUME 339

D

ECEMBER

10, 1998

NUMBER 24

UNRUPTURED INTRACRANIAL ANEURYSMS — RISK OF RUPTURE AND RISKS OF SURGICAL INTERVENTION

T

HE

I

NTERNATIONAL

S

TUDY

OF

U

NRUPTURED

I

NTRACRANIAL

A

NEURYSMS

I

NVESTIGATORS

*

A

BSTRACT

Background

The management of unruptured in-tracranial aneurysms requires knowledge of the nat-ural history of these lesions and the risks of repair-ing them.

Methods

A total of 2621 patients at 53 participat-ing centers in the United States, Canada, and Europewere enrolled in the study, which had retrospectiveand prospective components. In the retrospectivecomponent, we assessed the natural history of un-ruptured intracranial aneurysms in 1449 patientswith 1937 such aneurysms; 727 of the patients hadno history of subarachnoid hemorrhage from a dif-ferent aneurysm (group 1), and 722 had a history ofsubarachnoid hemorrhage from a different aneu-rysm that had been repaired successfully (group 2).In the prospective component, we assessed treat-ment-related morbidity and mortality in 1172 pa-tients with newly diagnosed unruptured intracranialaneurysms.

Results

In group 1, the cumulative rate of ruptureof aneurysms that were less than 10 mm in diameterat diagnosis was less than 0.05 percent per year, andin group 2, the rate was approximately 11 times ashigh (0.5 percent per year). The rupture rate of aneu-rysms that were 10 mm or more in diameter was lessthan 1 percent per year in both groups, but in group1, the rate was 6 percent the first year for giant an-eurysms (»25 mm in diameter). The size and loca-tion of the aneurysm were independent predictors ofrupture. The overall rate of surgery-related morbidityand mortality was 17.5 percent in group 1 and 13.6percent in group 2 at 30 days and was 15.7 percentand 13.1 percent, respectively, at 1 year. Age inde-pendently predicted surgical outcome.

Conclusions

The likelihood of rupture of unrup-tured intracranial aneurysms that were less than 10mm in diameter was exceedingly low among pa-tients in group 1 and was substantially higher amongthose in group 2. The risk of morbidity and mortalityrelated to surgery greatly exceeded the 7.5-year riskof rupture among patients in group 1 with unrup-tured intracranial aneurysms smaller than 10 mm indiameter. (N Engl J Med 1998;339:1725-33.)

©1998, Massachusetts Medical Society.

Address reprint requests to Dr. David O. Wiebers, at the ISUIA Coor-dinating Center, Mayo Clinic, 200 First St. SW, Rochester, MN 55905.

*The institutions and investigators participating in the study are listed inthe Appendix. On behalf of the Steering Committee, Dr. Wiebers assumesoverall responsibility for the content of the manuscript.

NTRACRANIAL aneurysms are common.

1-6

Autopsy studies have shown that the overallfrequency in the general population ranges from0.2 to 9.9 percent (mean frequency, approxi-

mately 5 percent),

5,6

suggesting that 10 to 15 millionpersons in the United States have or will have intra-cranial aneurysms. These data, in combination withthe incidence of aneurysmal subarachnoid hemor-rhage (approximately 10 cases per 100,000 personsper year),

7

suggest that most intracranial aneurysmsdo not rupture.

The management of unruptured intracranial an-eurysms is controversial

8-12

because of a lack of un-derstanding of the natural history of these lesions andthe risks of repairing them. This report describes alarge multicenter study that was conducted to deter-mine the risk of rupture and the risks associated withthe repair of unruptured intracranial aneurysms.

METHODS

Study Design and Objectives

The study consisted of a retrospective component based ondata from the medical records of patients with diagnosed unrup-tured intracranial aneurysms and a prospective component basedon data from patients with newly diagnosed unruptured intracra-nial aneurysms treated either conservatively or by surgical or en-dovascular procedures.

The specific objectives of the retrospective portion of the studywere to describe the natural history of saccular unruptured intra-cranial aneurysms in patients without a history of subarachnoidhemorrhage from a separate aneurysm (group 1) and in thosewith such a history (group 2), and to determine whether thereare subgroups of patients at greater risk for subsequent aneurys-mal rupture, in order to determine the most appropriate treat-

I

Copyright © 1998 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at UC SHARED JOURNAL COLLECTION on February 1, 2007 .

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December 10, 1998

The New England Journal of Medicine

ment of such patients. For the prospective portion of the study,the objectives were to evaluate the risks of morbidity and mortal-ity associated with treatment of unruptured intracranial aneu-rysms and to determine whether these risks are higher for somepatients than for others.

Identification and Recruitment of Patients

The retrospective cohort included patients with unruptured in-tracranial aneurysms that had been diagnosed during the periodfrom 1970 to 1991. At each center, retrospective cases could beincluded only as far back as hard-copy arteriograms and medicalrecords were available for all patients at that center. Central med-ical-records systems, admission records, and records from depart-ments of radiology, neurosurgery, and neurology were used assources for identifying patients.

Prospective patients were identified by study coordinators atthe participating centers, who conducted surveillance of patientswith diagnosed intracranial aneurysms between 1991 and 1995.

Patient Eligibility

Retrospective Component

Patients were eligible for enrollment in the retrospective com-ponent if they had had at least one unruptured intracranial aneu-rysm, whether or not they had symptoms (e.g., cranial-nerve pal-sy). Patients may have had a previous ruptured aneurysm atanother location that was clipped, completely trapped, or isolatedfrom the circulation by endovascular obliteration, as confirmedarteriographically. Patients had to have been able to care forthemselves after the previous aneurysm had been treated (i.e., ascore of 1 or 2 on the Rankin scale of neurologic disability, withscores ranging from 1 [no disability] to 5 [severe disability]).

Patients with fusiform, traumatic, or mycotic aneurysms werenot eligible for the study. Also, patients with aneurysms that werefound to be less than 2 mm in maximal diameter with the use ofa standard measuring device were excluded. Patients with sub-arachnoid hemorrhage from a single ruptured aneurysm or anunknown source were excluded. In addition, patients in whomthe aneurysm was manipulated within 30 days after diagnosiswere not eligible. Patients with a history of intracranial hemor-rhage were excluded if the cause was unknown or if an underlyingstructural lesion was not repaired. Patients were excluded if theydid not consent to follow-up, if they had a malignant brain tumor,or if they were bedridden or unable to communicate at the timethe aneurysm was identified.

Prospective Component

Eligibility criteria for patients in the prospective componentwere similar to those for the patients in the retrospective compo-nent, except that in the prospective component, the investigatorsdecided whether to enroll the patients without planned surgicalor endovascular treatment or with planned surgical or endovascu-lar treatment of at least one intracranial aneurysm. All patientswere required to undergo cerebral arteriography in order to con-firm the presence, location, and size of intracranial aneurysms.

Radiology

Hard copies of cerebral arteriograms from all patients were re-viewed at the central study office at the Mayo Clinic, Rochester,Minnesota, by two neuroradiologists. The size of the aneurysmwas corrected for magnification by methods reported previous-ly.

13

A pilot study was conducted to establish criteria for measure-ment, standards for evaluating the size and morphologic charac-teristics of the aneurysm, and interobserver reliability.

13

Follow-up

For the retrospective cohort, follow-up information was ob-tained by means of an annual standardized questionnaire and a

review of medical records. Neurologic symptoms, intracranial sur-gery, or repeated arteriographic studies undertaken since the pre-vious assessment were recorded.

For the prospective cohort, base-line assessments were made.Prospective patients who did not undergo planned surgical treat-ment were followed with the use of an annual questionnaire. Forpatients who underwent surgical treatment, assessments were made7 days after the procedure, at hospital discharge, at 30 days, andat yearly intervals. For both cohorts, neurologic status was meas-ured with the use of the Rankin scale at each follow-up assess-ment, and cognitive status was determined with the Mini–MentalState Examination

14

or the Telephone Interview for CognitiveStatus

15

at the same intervals. All complications of surgical treat-ment were recorded.

Determination of Events

Detailed information was obtained on all end points (definiteor questionable subarachnoid or intracerebral hemorrhage anddeath). Comprehensive adjudication was performed centrally forall hemorrhages, strokes, and deaths on the basis of uniform cri-teria, with the use of available clinical, radiologic, autopsy, andother information, and hemorrhages were classified according tothe location of the rupture. Subarachnoid or intracerebral hem-orrhage was classified as definite (symptoms of subarachnoid orintracerebral hemorrhage and positive findings on computed to-mography [CT] or magnetic resonance imaging [MRI], surgery,or autopsy), highly probable (symptoms and positive findings oncerebrospinal fluid analysis), or probable (symptoms only). Alldefinite, highly probable, and probable aneurysmal hemorrhageswere included in the primary analysis.

In the prospective component of the study, evidence of sur-gery-related cerebral infarction, hemorrhage, or death was con-firmed centrally. Neurologic deficits 30 days or 1 year after treat-ment were evaluated for their relation to treatment or coexistingdisorders.

Morbidity related to surgical treatment was defined as a Rankinscore of 3, 4, or 5 (moderate-to-severe neurologic disability) or ascore of less than 24 on the Mini–Mental State Examination orless than 27 on the Telephone Interview for Cognitive Status(both indicating a serious cognitive abnormality) at 30 days and1 year.

14-16

Mortality was considered separately.

Statistical Analysis

The retrospective component included two groups designatedby their eligibility for enrollment. Group 1 and group 2 were an-alyzed as separate strata. Between-group comparisons of the dis-tributions of demographic and clinical characteristics were madeby the chi-square test for categorical variables and the t-test forcontinuous variables. Estimates of the risk of hemorrhage weremade with the use of life-table methods, with data on death, sur-gical intervention, and last follow-up assessment censored. Pre-dictors of hemorrhage were ascertained with the use of a propor-tional-hazards regression model.

For the prospective cohort, survival, morbidity (a Rankin scoreof 3, 4, or 5), and diminished mental status (a score of less than24 on the Mini–Mental State Examination or less than 27 on theTelephone Interview for Cognitive Status), as well as overall mor-bidity and mortality, were analyzed. Survival estimates and 95percent confidence intervals were calculated with life-table meth-ods 30 days and 1 year after treatment. The risk of morbidity wasestimated as the proportion of patients with impairment at the30-day and 1-year examinations. The overall risk of morbidity ormortality was estimated as the proportion of patients who weredisabled or dead at 30 days and at 1 year. Surgery-related morbid-ity and mortality were estimated on the basis of only those eventsattributed to treatment of the aneurysm. Factors related to overallmorbidity and mortality were determined with the use of logisticregression. (An expanded description of the methods used in thisstudy is available on the Internet at www.mayo.edu/ISUIA or bywriting to the ISUIA Coordinating Center.)




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RESULTS

Retrospective Cohort

Demographic and Clinical Characteristics

Fifty-three centers in the United States, Canada,and Europe enrolled a total of 1449 patients with1937 unruptured intracranial aneurysms (727 pa-tients in group 1 and 722 patients in group 2). Theaneurysms were diagnosed at the participating cen-ters between 1970 and 1991.

Of the 1449 patients, 1085 (75 percent) had sin-gle unruptured intracranial aneurysms and 364 (25percent) had multiple unruptured intracranial aneu-rysms, with similar distributions in groups 1 and 2(Table 1). The mean age at diagnosis was higher ingroup 1 than in group 2 (Table 1). Almost threefourths of the patients were women. The mean du-ration of follow-up was 8.3 years, with a total of ap-proximately 12,023 patient-years of follow-up.

Conditions leading to the diagnosis of unrup-tured intracranial aneurysms included headaches in36 percent of patients, ischemic cerebrovascular dis-ease in 17.6 percent, cranial-nerve deficits in 15.4percent, aneurysmal mass effect in 5.7 percent, ill-defined spells in 4.8 percent, convulsive disorder in4.2 percent, subdural or intracerebral hemorrhage in2.7 percent, brain tumor in 1.7 percent, and nervous

system degenerative disease in 0.5 percent. The di-agnosis was suspected on the basis of CT findings in39.8 percent and MRI findings in 5.6 percent.

Aneurysmal Characteristics

The distribution of unruptured intracranial aneu-rysms according to size and location (parent artery)is shown for groups 1 and 2 in Table 1. Forty-one ofthe patients in group 1 with small aneurysms (<10mm in diameter) (9.7 percent) and 153 patients inthe entire retrospective group (10.6 percent) hadsingle cavernous carotid aneurysms.

Overall, 32 percent of the patients in group 1 and11 percent of those in group 2 had unruptured an-eurysms that caused symptoms other than those as-sociated with rupture (e.g., cranial-nerve palsies).

Risk Factors

Potential risk factors for the development of anunruptured aneurysm or for subsequent rupturewere documented at the time of diagnosis (Table 2).Among patients for whom data on smoking wereavailable, 60.6 percent were current smokers and18.6 percent were former smokers (a precise historyof smoking was unavailable for 31 percent of the pa-tients). Other potential risk factors for which therewere substantial numbers of patients with missing

*Patients in group 1 had no history of subarachnoid hemorrhage, and those in group 2 had a his-tory of subarachnoid hemorrhage.

†NS denotes not significant.

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ABLE

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ASE

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INE

C

HARACTERISTICS

OF

THE

R

ETROSPECTIVE

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OHORT

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C

HARACTERISTIC

G

ROUP

1 (N=727)

G

ROUP

2 (N=722) P V

ALUE

Age — yrMeanRange

56.09–87

49.413–80

<0.001

Female sex — no. of patients (%) 517 (71.1) 535 (74.1) 0.27White race — no. of patients (%) 669 (92.0) 681 (94.3) 0.08Single aneurysm — no. of patients (%) 545 (75.0) 540 (74.8) NS†Multiple aneurysms — no. of patients (%)Total no. of aneurysms

182 (25.0)977

182 (25.2)960

Diameter of largest aneurysm — mmMeanRange

10.92–60

5.72–35

<0.001

Size of largest aneurysm — no. of patients (%)2–5 mm6–9 mm10–14 mm15–24 mm»25 mm

238 (32.7)186 (25.6)113 (15.5)120 (16.5)70 (9.6)

442 (61.2)199 (27.6)65 (9.0)13 (1.8)3 (0.4)

0.001

Location of aneurysm — no. of aneurysms (%)Cavernous carotid arteryInternal carotid arteryAnterior communicating or anterior cerebral

arteryMiddle cerebral arteryPosterior communicating arteryVertebrobasilar or posterior cerebral arteryTip of basilar artery

165 (16.9)242 (24.8)98 (10.0)

222 (22.7)136 (13.9)64 (6.6)50 (5.1)

91 (9.5)171 (17.8)79 (8.2)

363 (37.8)163 (17.0)56 (5.8)37 (3.9)

<0.001<0.001

0.22

<0.0010.060.510.18


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data on retrospective review included alcohol con-sumption and the use of oral contraceptives andstimulants.

Aneurysmal Rupture

Of the 1449 patients, 32 had confirmed aneurys-mal ruptures during follow-up, and in 28 of the 32,the rupture occurred within the first 7.5 years of fol-low-up. Two other patients with subarachnoid hem-orrhage 2 years and 5.6 years after diagnosis hadcoexisting arteriovenous malformations. In neitherpatient was it possible to delineate whether the an-eurysm or the arteriovenous malformation had rup-tured. Patients with both aneurysms and arteriove-nous malformations (20 in group 1 and 13 in group2) were not included in the analysis of end points.Of the 12 patients in group 1 who had confirmedaneurysmal subarachnoid hemorrhage, only 1 hadan aneurysm that was less than 10 mm in diameter,whereas 17 of the 20 patients in group 2 with rup-tures had aneurysms that were less than 10 mm indiameter. Two of the 32 ruptures occurred in pa-tients with cavernous carotid aneurysms.

Prediction of Rupture

In group 1, the only significant predictors of rup-ture were the size and location of the aneurysm. An-

eurysms that were less than 10 mm in diameter weremuch less likely to rupture than those that were 10to 24 mm in diameter (relative risk for larger aneu-rysms, 11.6; P=0.03) or 25 mm or more in diame-ter (relative risk, 59.0; P<0.001). The relative risk ofrupture was 13.8 for aneurysms at the basilar tip and13.6 for those in the vertebrobasilar or posteriorcerebral distribution, as compared with other loca-tions (P=0.001 and P=0.007, respectively). For pos-terior communicating aneurysms, the relative risk ofrupture was 8.0 (P=0.02). In group 2, the relativerisk of rupture was 5.1 for aneurysms at the basilartip (P=0.004) and 1.31 for older age (P=0.04).The size of the aneurysm did not predict the risk ofrupture.

Rupture Rates

Rates of confirmed subarachnoid hemorrhage 7.5years after diagnosis are shown in Figures 1 and 2.The cumulative rate of rupture for patients in group1 with aneurysms that were less than 10 mm in di-ameter at the time of discovery was 0.4 percent, orabout 0.05 percent per year. In contrast, the rupturerate for patients in group 1 with aneurysms thatwere 10 mm or more in diameter was about 20times that of the rate for smaller aneurysms, ap-proaching 1 percent per year (Fig. 1). In group 2,

T

ABLE

2.

R

ISK

F

ACTORS

FOR

R

UPTURE

IN

THE

R

ETROSPECTIVE

AND

P

ROSPECTIVE

C

OHORTS

.

C

OHORT

AND

R

ISK

F

ACTOR

G

ROUP

1 G

ROUP

2 T

OTAL

no./total no. (%)

Retrospective cohortHypertensionTreatment for hypertensionAtrial fibrillationCardiac arrhythmiasCongestive heart failureMyocardial infarctionValvular diseaseAlcohol use (>5 drinks in 24 hr)Current smokerFormer smokerUse of stimulantsUse of oral contraceptives by women

308/697 (44.2)264/698 (37.8)16/691 (2.3)41/688 (6.0)15/695 (2.2)39/689 (5.7)11/691 (1.6)38/202 (18.8)

284/540 (52.6)120/540 (22.2)

4/129 (3.1)38/143 (26.6)

200/676 (29.6)124/698 (17.8)

4/673 (0.6)16/673 (2.4)2/673 (0.3)

21/671 (3.1)2/673 (0.3)

74/155 (47.7)321/459 (69.9)66/459 (14.4)6/125 (4.8)

31/94 (33.0)

508/1373 (37.0)388/1396 (27.8)20/1364 (1.5)57/1361 (4.2)17/1368 (1.2)60/1360 (4.4)13/1364 (1.0)

112/357 (31.4)605/999 (60.6)186/999 (18.6)10/254 (3.9)69/237 (29.1)

Prospective cohortHypertensionTreatment for hypertensionAtrial fibrillationCardiac arrhythmiasCongestive heart failureMyocardial infarctionValvular diseaseAlcohol use (>5 drinks in 24 hr)Current smokerFormer smokerUse of stimulantsUse of oral contraceptives by women

295/798 (37.0)251/798 (31.5)22/798 (2.8)45/798 (5.6)5/798 (0.6)

32/798 (4.0)17/798 (2.1)

244/798 (30.6)359/798 (45.0)255/798 (32.0)63/798 (7.9)

285/579 (49.2)

70/197 (35.5)54/197 (27.4)0/197 5/197 (2.5)0/197 7/197 (3.6)3/197 (1.5)

71/197 (36.0)106/197 (53.8)61/197 (31.0)15/197 (7.6)98/159 (61.6)

365/995 (36.7)305/995 (30.7)22/995 (2.2)50/995 (5.0)5/995 (0.5)

39/995 (3.9)20/995 (2.0)

315/995 (31.7)465/995 (46.7)316/995 (31.8)78/995 (7.8)

383/738 (51.9)




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the smaller aneurysms were approximately 11 timesas likely to rupture as aneurysms of the same size ingroup 1, with a rate of approximately 0.5 percent peryear. The rupture rate of larger aneurysms was simi-lar to that in group 1, approaching 1 percent peryear. Figure 2 shows rupture rates over time forgroups 1 and 2 according to the size of the aneu-rysm. In group 1, aneurysms that were 25 mm ormore in diameter had a rupture rate of 6 percent inthe first year (Fig. 2A).

Mortality

Among the 32 patients with initially unrupturedaneurysms and subsequent hemorrhage, the case fa-tality rate was 66 percent (83 percent in group 1 and55 percent in group 2). Of the 205 patients whodied during the 7.5 years of follow-up, 42 died of in-tracranial hemorrhage, 36 of cancer, 30 of cardiacdisease, 14 of respiratory tract disease, 11 of cerebralinfarction, and 72 of other, unrelated causes. On anactuarial basis, the estimated survival rate at five yearsfor the entire retrospective cohort was 89 percent.

Prospective Cohort

Surgical Intervention

In the prospective cohort, 1172 patients were en-rolled in the treatment group (961 patients in group1 and 211 in group 2). Intracranial surgery was per-formed in 798 patients (83 percent) in group 1 andin 198 (94 percent) in group 2. The rest of the pa-tients were treated with various endovascular proce-dures.

Demographic and Clinical Characteristics

The mean age at diagnosis was 52 years (range, 19to 91), with a higher mean age in group 1 than in

group 2 (53 vs. 47 years) (Table 3). Approximatelythree fourths of the patients were women.

Conditions leading to the diagnosis of an unrup-tured intracranial aneurysm and enrollment in thetreatment group included headache in 34 percent ofpatients, cranial-nerve deficits in 14 percent, ische-mic cerebrovascular disease in 11 percent, ill-definedspells in 10 percent, aneurysmal mass effect in 6 per-cent, convulsive disorder in 5 percent, subdural orintracerebral hemorrhage in 0.4 percent, brain tu-mor in 0.4 percent, and nervous system degenerativedisease in 0.3 percent. The diagnosis was suspectedon the basis of CT findings in 40 percent of patientsand MRI findings in 37 percent.

Figure 1.

Probability of Subarachnoid Hemorrhage 7.5 Years af-ter the Diagnosis of Unruptured Intracranial Aneurysm, Ac-cording to the Diameter of the Aneurysm.Patients in group 1 had no history of subarachnoid hemorrhagefrom a different aneurysm, and those in group 2 did have sucha history. Data are from the retrospective cohort. The bars rep-resent 95 percent confidence intervals.

0.00

0.12

<10 mm »10 mm <10 mm »10 mm

0.02

0.04

0.06

0.08

0.10

Group 2Group 1

Pro

bab

ility

of

Hem

orr

hag

e

Figure 2.

Probability of Subarachnoid Hemorrhage over Time inGroup 1 (Panel A) and Group 2 (Panel B), According to the Sizeof the Aneurysm.In Panel B, no rates are shown for aneurysms in the largest cat-egory (»25 mm) because there were only three patients withaneurysms in this category. The numbers at the bottom of eachpanel are the numbers of patients not operated on who wereat risk for a first hemorrhage. Data are from the retrospectivecohort.

0.00

0.14

0

0.02

0.04

0.06

0.08

0.10

0.12

71 2 3 4 5 6

Years after Diagnosis

Group 1

<10 mm

10–24 mm

»25 mm

NO. AT RISK 446 417 395 373 345 295 242

Pro

bab

ility

of

Hem

orr

hag

e

0.00

0.14

0

0.02

0.04

0.06

0.08

0.10

0.12

71 2 3 4 5 6

Years after Diagnosis

Group 2

<10 mm

10–24 mm

NO. AT RISK 438 409 391 371 344 305 264

Pro

bab

ility

of

Hem

orr

hag

e

B

A


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December 10, 1998


T

ABLE

3.

B

ASE

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HARACTERISTICS

OF

THE

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ROSPECTIVE

C

OHORT

.

C

HARACTERISTIC

G

ROUP

1 (N=798)

G

ROUP

2 (N=197) P V

ALUE

Age — yrMeanRange

53.019–91

47.224–78

<0.001

Female sex — no. of patients (%) 598 (74.9) 163 (82.7)White race — no. of patients (%) 735 (92.1) 175 (88.8)Total no. of aneurysms 1039 262Diameter of largest aneurysm — mm

MeanRange

11.62–50

8.32–60

Size of largest aneurysm — no. of patients (%)2–5 mm6–9 mm10–14 mm15–24 mm»25 mm

128 (16.0)262 (32.8)203 (25.4)148 (18.5)57 (7.1)

65 (33.0)79 (40.1)39 (19.8)11 (5.6)3 (1.5)

<0.001

Location of aneurysm — no. of aneurysms (%)Cavernous carotid arteryInternal carotid arteryAnterior communicating or anterior cerebral

arteryMiddle cerebral arteryPosterior communicating arteryVertebrobasilar or posterior cerebral arteryTip of basilar artery

24 (2.3)393 (37.8)167 (16.1)

305 (29.4)43 (4.1)50 (4.8)57 (5.5)

3 (1.1)82 (31.3)23 (8.8)

116 (44.3)15 (5.7)15 (5.7)8 (3.1)

0.240.050.003

<0.0010.270.540.11

Aneurysmal Characteristics

The distribution of unruptured intracranial aneu-rysms according to size and location (parent artery)is shown for groups 1 and 2 in Table 3. The distri-butions of aneurysms were very similar to those inthe retrospective cohort.

Overall, 21 percent of the patients had specificsymptoms, including 23 percent of the patients ingroup 1 and 10 percent of those in group 2.

Risk Factors

Various potential risk factors for the developmentof an intracranial aneurysm as well as treatment-related morbidity and mortality were documented atthe time of diagnosis (Table 2). Overall, 47 percentof the patients were current smokers, and 32 percentwere former smokers.

With regard to base-line neurologic status, 94 per-cent of the patients had a Rankin score of 1 (96 per-cent in group 1 and 89 percent in group 2). TheBarthel score was 100 (indicating normal ability toperform the activities of daily living) for 98 percentof patients, and the score on the Mini–Mental StateExamination was higher than 23 (indicating no seri-ous cognitive abnormality) for 98 percent of the pa-tients.

Surgical Outcome

The morbidity and mortality rates at 30 days and1 year are shown in Table 4. Thirty days after surgery,

18 of 996 patients (all in group 1) had died. Tendeaths were due to cerebral infarction, five to intra-cranial hemorrhage, and two to pulmonary embo-lism; one death was related to respiratory complica-tions. One year after surgery, 34 deaths had occurredin group 1 (30 related to surgery) and 2 in group 2(both related to surgery).

Seventy-eight patients in group 1 and eight ingroup 2 had a Rankin score of 3, 4, or 5 at 30 days.Ninety-three patients in group 1 and 21 in group 2had impaired cognitive status.

Age was the only independent predictor of a poorsurgical outcome. In group 1, surgery-related mor-bidity and mortality at one year among patientsyounger than 45 years was 6.5 percent, as comparedwith 14.4 percent for those between 45 and 64 yearsold and 32 percent for those over 64 (P<0.001).

DISCUSSION

Among patients without a history of subarach-noid hemorrhage (group 1), those with unrupturedintracranial aneurysms that were less than 10 mm indiameter had an exceedingly low risk of rupture (ap-proximately 0.05 percent per year). Unruptured an-eurysms of the same size in patients with a historyof subarachnoid hemorrhage (group 2) were ap-proximately 11 times as likely to rupture (a risk ofapproximately 0.5 percent per year). The size and lo-cation of the aneurysm were significant independentpredictors of rupture in patients in group 1 (larger




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1731

aneurysms and those in the tip of the basilar artery,vertebrobasilar or posterior cerebral artery, or poste-rior communicating artery were more likely to rup-ture). In group 2, only the basilar-tip location waspredictive of rupture. In view of these findings, it ispertinent to begin considering patients with previ-ous subarachnoid hemorrhage and those withoutprevious hemorrhage differently when making deci-sions about the management of unruptured intracra-nial aneurysms.

The overall rupture rate for the 1449 patients inthe retrospective component of our study (0.5 per-cent per year) was lower than the rates reported inprevious natural-history studies,

8,17

and the rate ingroup 1 was significantly lower than that in group 2.The aneurysms were considerably larger in group 1(mean diameter, 10.9 mm) than in group 2 (meandiameter, 5.7 mm), and the number of giant aneu-rysms was markedly lower in group 2. These differ-ences are most likely the result of the rupture or re-pair (or both) of larger aneurysms in the patients ingroup 2 before enrollment in the study. The exceed-ingly low rupture rate in the patients in group 1 withaneurysms that were less than 10 mm in diameter isconsistent with the findings of previous studies.

8,9

Although the retrospective component of ourstudy provides indispensable long-term follow-updata as a basis for determining future rupture rates,

it is possible that a systematic bias we cannot identifyhas been introduced because of the nature of thiscohort.

The overall morbidity and mortality rates associ-ated with surgical repair of unruptured intracranialaneurysms were higher than those reported previ-ously. The 30-day rates of mortality and morbidity(a score of 3, 4, or 5 on the Rankin scale) were onlyslightly higher than those predicted on the basis ofa systematic review of previous reports on repair ofunruptured aneurysms.

18-23

In our study, however,impaired mental status added substantially to mor-bidity at 30 days and 1 year, and this variable was notassessed in the previous studies.

The lower rates of treatment-related mortality andneurologic morbidity (as measured by the Rankinscore) in group 2 are probably the result of the se-lection of survivors of a first subarachnoid hemor-rhage and a craniotomy performed to repair a rup-tured aneurysm. However, patients in group 2 weremore likely to have a deterioration in mental status,which may have resulted from three consecutive cer-ebral events (one subarachnoid hemorrhage and twocraniotomies) as compared with only one event (cra-niotomy) in most patients in group 1.

In the surgically treated cohort, age was the onlysignificant independent predictor of surgical out-come. The rates of surgery-related morbidity and

*CI denotes confidence interval.

†Normal neurologic status was defined as a Rankin score of 1 and no cognitive impairment asmeasured by the Mini–Mental State Examination. There were 764 patients in group 1 and 188 ingroup 2 who had normal neurologic status at base line.

T

ABLE

4

. S

URGICAL

O

UTCOME

IN GROUP 1 AND GROUP 2.*

OUTCOME GROUP 1 (N=798) GROUP 2 (N=197)

NO. OF

PATIENTS % (95% CI)NO. OF

PATIENTS % (95% CI)

At 1 mo

Surgery-related death 18 2.3 (1.3–3.3) 0 0 (0–1.4)Disability

Rankin score of 3–5 onlyImpaired cognitive status onlyBoth

122294449

15.33.65.56.1

276

192

13.73.09.61.0

Overall morbidity and mortalityAll patientsPatients with normal neurologic

status at base line†

140130

17.5 (15.5–20.5)17.0

2724

13.6 (8.0–17.2)12.8

At 1 yr

Surgery-related death 30 3.8 (2.4–5.4) 2 1.0 (0–2.6)Disability

Rankin score of 3–5 onlyImpaired cognitive status onlyBoth

95264326

12.03.35.43.3

243

183

12.11.59.11.5

Overall morbidity and mortalityAll patientsPatients with normal neurologic

status at base line†

125119

15.7 (13.2–18.2)15.6

2621

13.1 (8.0–17.2)11.2


1732 · December 10, 1998


mortality were substantially lower for younger pa-tients than for older patients. Other potential predic-tors of surgery-related morbidity and mortality (in-cluding the location and size of the aneurysm) andendovascular results could not be assessed adequatelywith the number of patients in the prospective cohort.

With aneurysmal size and location included in themultivariate model, the presence of aneurysmal symp-toms other than those related to rupture was not apredictor of rupture. Similarly, the presence of symp-toms did not independently predict the outcome ofsurgery.

The management of unruptured intracranial an-eurysms depends on the natural history of these le-sions and on morbidity and mortality rates associat-ed with repair. On the basis of the rupture rates andtreatment risks in our study, it appears unlikely thatsurgery will reduce the rates of disability and deathin patients with unruptured intracranial aneurysmssmaller than 10 mm in diameter and no history of sub-arachnoid hemorrhage. Data on treatment-relatedmorbidity and mortality rates according to aneurys-mal size and location and specific symptoms are re-quired to determine whether surgical or endovascularintervention may be warranted in various subgroupsof patients with unruptured intracranial aneurysms,including those with acutely symptomatic unrup-tured aneurysms.

Supported by a grant (R01-NS-28492) from the National Institute ofNeurological Disorders and Stroke.

APPENDIX

The following investigators participated in the International Study ofUnruptured Intracranial Aneurysms (SC denotes Steering Committee, andEC Executive Committee): Central Office — Rochester, Minn.: D. Wiebers(SC, EC), principal investigator; J. Whisnant (SC, EC), co–principal inves-tigator — neurology; G. Forbes (SC, EC), co–principal investigator — ra-diology; I. Meissner (SC, EC), investigator — neurology; R. Brown, Jr.(SC, EC), investigator — neurology; D. Piepgras (SC), investigator — neu-rosurgery; J. Huston III (SC, EC), investigator — radiology; D. Nichols(SC, EC), investigator — radiology; W. O’Fallon (SC, EC), investigator —statistics; J. Peacock (SC), administrator; L. Jaeger (SC), assistant adminis-trator; Methods Center — Charlottesville, Va.: N. Kassell (SC, EC), co–principal investigator — neurosurgery; G. Kongable-Beckman (SC), datacoordinator; Statistical Center — Iowa City, Iowa: J. Torner (SC, EC), co–principal investigator — statistics; M. Rajput, data analysis; additional Ex-ecutive Committee members — London, Ont., Canada: C. Drake; Washing-ton, D.C.: J. Kurtzke; National Institute of Neurological Disorders andStroke: J. Marler, M. Walker.

In addition to the investigators listed above, the following investigatorsparticipated in the study: Rochester, Minn.: F. Meyer, J. Atkinson, W. Marsh,K. Thielen; London, Ont., Canada: G. Ferguson (EC), H. Barr, S. Lownie,V. Hachinski, A. Fox, R. Sahjpaul, A. Parrent, C. Mayer; Glasgow, Scotland:K. Lindsay, E. Teasdale, I. Bone, J. Fatukasi, M. Lindsay; Charlottesville,Va.: W. Cail, Jr., O. Sagher, M. Davis; Newcastle upon Tyne, United King-dom: R. Sengupta (EC), D. Bates, A. Gholkar, J. Murdy, S. Wilson, S. Pra-haraj, G. Partridge, C. Reynolds, N. Hind; Boston: C. Ogilvy, R. Crowell,D. Gress, P. Schaefer, I. Choi, D. Buckley, K. Sloan, D. King; Los Angeles(USC ): S. Giannotta, S. Ameriso, G. Teitelbaum, E. Thomson, D. Fish-back; Budapest, Hungary: J. Vajda, I. Nyáry, S. Czirják, M. Horváth, I. Szi-kora, E. Pásztor, P. Várady, A. Erdos; Stockholm, Sweden: G. Edner (EC),N. Wahlgren, M. Lindqvist, A. Antonsson; Verona, Italy: R. Da Pian, A.Pasqualin, F. Chioffi, A. Beltramello, G. Zampieri, A. Benati, G. Rossi;Kuopio, Finland: A. Ronkainen, J. Hernesniemi, M. Vapalahti, J. Rinne, M.Luukkonen, M. Vihavainen, S. Savolainen, T. Koivisto, S. Leivo, K. Helin;Stanford, Calif.: G. Steinberg, M. Marks, M. Vanefsky, A. Norbash, R.Thompson, T. Bell, M. Marcellus, A. Meyer; Oxford, United Kingdom: R.

Kerr, C. Adams, A. Molyneux (EC), S. Vinden, F. Bacon, J. Shrimpton, S.Parker; Gainesville, Fla.: A. Day, S. Nadeau, J. Stachniak, W. Friedman, R.Fessler, K. Peters, R. Jacob, S. Roper, A. Smith, P. LaFrentz; Iowa City,Iowa: M. Howard, C. Loftus, H. Adams, Jr., D. Crosby, M. Rogers; Cin-cinnati: J. Broderick, J. Tew, Jr., T. Brott, H. van Loveren, H. Yeh, M. Zuc-carello, T. Tomsick, M. Gaskill-Shipley, L. Minneci, N. McMahon; Bor-deaux, France: J. Castel (EC), J. Orgogozo, H. Loiseau, P. Bourgeois, J.Berge, V. Dousset, E. Cuny; Ottawa, Ont., Canada: M. Richard, C. Agbi,H. Hugenholtz, B. Benoit, W. Morrish, R. Wee, S. Grahovac, L. Pratt, M.Mortensen; Bologna, Italy: A. Andreoli (EC), C. Testa, V. Comani, C. Tre-visan, P. Limoni, F. Carlucci, M. Leonardi, C. Sturiale; Graz, Austria: G.Pendl, H. Eder, G. Klein, M. Eder, K. Leber; Indianapolis: T. Horner, T.Leipzig, T. Payner, A. Denardo, J. Scott, K. Redelman; Birmingham, Ala.:W. Fisher III, M. Rosner, G. Vitek, M. Hand, W. Flack; Paris: J. Sichez, B.Pertuiset, D. Fohanno, C. Marsault, A. Casasco, A. Biondi, L. Capelle, H.Duffau; Seattle: H. Winn, M. Grady, D. Newell, W. Longstreth, P. Thomp-son, H. Bybee, D. Jones; Edmonton, Alta., Canada: J. Findlay, K. Petruk,D. Steinke, R. Ashforth, P. Stenerson, D. Schindel, H. Vanderhoven, J.Neves; Philadelphia: E. Zager, E. Flamm, E. Raps, R. Hurst, S. Parrott, M.Sellers, M. Torchia; Winnipeg, Man., Canada: B. Anderson, M. West, D.Fewer, N. Hill, G. Sutherland, I. Ross, B. McClarty, R. Brownstone, O.Williams, P. Narotam, L. Christane, G. McGinn, D. Gladish; Cambridge,United Kingdom: P. Kirkpatrick, J. Pickard, N. Antoun, D. Simpson, N.Higgins, C. Turner, S. Tebbs; Halifax, N.S., Canada: R. Holness, D. Mal-loy, S. Phillips, W. Maloney, V. Molina-de-Orozco, B. Baxter, K. Connolly-Campbell, A. MacDougall; Toronto: F. Gentili, M. Wallace, K. ter Brugge,R. Willinsky, M. Tymianski, L. Rickards, W. Tucker, C. Lambert, W. Mon-tanera, C. Rychlewski, C. Flood; Milan, Italy (UM ): R. Villani, E. Sganzerla,G. Tomei, A. Bettinelli, M. Leonardi, G. Ceccarelli, A. Righini, L. Bello,C. Marras; Bristol, United Kingdom: R. Nelson, T. Lewis, C. Renowden,Y. Clarke, L. Varian; Cleveland: D. Chyatte, C. Sila, J. Perl, T. Masaryk, R.Porterfield; Liverpool, United Kingdom: M. Shaw, P. Foy, T. Nixon, L.Dunn, N. Clitheroe, T. Smith, P. Eldridge, P. Humphrey, J. Wiseman, K.Hawkins, L. Owen, K. Ost, S. Saminaden; Montreal: G. Mohr, R. Schon-dorf, J. Carlton, M. Maleki, N. Just, S. Brien, S. Entis, D. Tampieri, N.Simons; Groningen, the Netherlands: J. Mooij, J. Metzemaekers, J. Hew, J.Beks, A. van der Veen, I. Bosma, M. Sprengers; Utrecht, the Netherlands:G. Rinkel, J. van Gijn, L. Ramos, C. Tulleken, P. Greebe, F. van Vliet;Copenhagen, Denmark: S. Borgesen, B. Jespersen, T. Boge-Rasmussen, L.Willumsen; Evanston, Ill.: D. Homer, T. Eller, J. Carpenter, J. Meyer, R.Munson, B. Small; Minneapolis: E. Nussbaum, R. Heros, R. Latchaw, P.Camarata, J. Lundgren, N. Mattsen; Edinburgh, Scotland: I. Whittle, R.Sellar, M. O’Sullivan, A. Steers, P. Statham, G. Malcolm, R. Price, B. Hoff-man; Pittsburgh: H. Yonas, L. Wechsler, J. Thompson-Dobkin, C. Jungreis,A. Kassam, L. Kirby; Jackson, Miss.: A. Parent, A. Lewis, P. Azordegan, R.Smith, L. Alexander, D. Gordon, W. Russell, R. Brown, G. Benashvili, R.Perry, D. Scalzo, G. Mandybur, C. Morgan; Marshfield, Wis.: P. Karanjia,K. Madden, D. Kelman, T. Gallant, H. Vanderspek, A. Choucair, J. Neal,K. Mancl; Lund, Sweden: H. Säveland, L. Brandt, S. Holtås, B. Trulsson;Chicago (UC): R. Macdonald, B. Weir, S. Mojtahedi, C. Amidei; Amster-dam: M. Vermeulen, D. Bosch, F. Hulsmans, K. Albrecht, Y. Roos, A. Vet,A. Gorissen, M. Mechielsen; Los Angeles (UCLA): N. Martin, Y. Gobin, J.Saver, F. Vinuela, G. Duckwiler, D. Kelly, J. Frazee, R. da Graca, T. Gravori;London (CCH): R. Illingworth, P. Richards, J. Wade, I. Colquhoun, E.Bashir, S. Shortt; Worcester, Mass.: J. Weaver, M. Fisher, B. Stone, S.Chaturvedi, R. Davidson, K. Davidson; Milan, Italy (CB): S. Giombini, C.Solero, A. Boiardi, C. Cimino, S. Valentini, A. Silvani; Durham, N.C.: M.Alberts, A. Friedman, A. Gentry, K. Hoffman; Denver: R. Hughes, K. Lil-lihei, M. Earnest, J. Nichols, G. Kindt, A. Anderson, S. Levy, J. Nichols,R. Smith, R. Breeze, V. Noonan; San Francisco: D. Gress, C. Dowd, J. Van-westrop, C. Wilson, M. Berger, L. Hannegan; Miami: R. Heros, J. Marcos,L. Ugarte; London, (QS): N. Kitchen, W. Taylor, M. Kumar, J. Grieve;Vancouver, B.C., Canada: F. Durity, M. Boyd, D. Fairholm, D. Griesdale,C. Honey, G. Redekop, B. Toyota, I. Turnbull, W. Woodhurst, T.Zwimpfer, P. Teal, D. Grabe, A. Brevner; Mannheim, Germany: A. Piepgras,P. Schmiedek, A. Schwartz, T. Weber; Chicago (NW ): J. Biller, S. Brem, G.Cybulski, L. Chadwick, K. Bronstein; Berlin, Germany: T. Pietilä, M. Brock,D. Krug, I. Krznaric; Helsinki, Finland: J. Hernesniemi, R. Kivisaari.

A full listing of investigators, committees, and institutions is available onthe Internet at www.mayo.edu/ISUIA.

REFERENCES

1. Chason JL, Hindman WM. Berry aneurysms of the circle of Willis: results of a planned autopsy study. Neurology 1958;8:41-4.2. Housepian EM, Pool JL. A systematic analysis of intracranial aneurysms from the autopsy file of the Presbyterian Hospital, 1914 to 1956. J Neu-ropathol Exp Neurol 1958;17:409-23.3. Stehbens WE. Aneurysms and anatomical variation of cerebral arteries. Arch Pathol 1963;75:45-64.



Volume 339 Number 24 · 1733

4. McCormick WF, Acosta-Rua GJ. The size of intracranial saccular aneu-rysms: an autopsy study. J Neurosurg 1970;33:422-7.5. Jellinger K. Pathology of intracerebral hemorrhage. Zentralbl Neuro-chir 1977;38:29-42.6. Jakubowski J, Kendall B. Coincidental aneurysms with tumours of pituitary origin. J Neurol Neurosurg Psychiatry 1978;41:972-9.7. Ingall TJ, Whisnant JP, Wiebers DO, O’Fallon WM. Has there been a decline in subarachnoid hemorrhage mortality? Stroke 1989;20:718-24.8. Wiebers DO, Whisnant JP, Sundt TM Jr, O’Fallon WM. The signifi-cance of unruptured intracranial saccular aneurysms. J Neurosurg 1987;66:23-9.9. Wiebers DO, Whisnant JP, O’Fallon WM. The natural history of unrup-tured intracranial aneurysms. N Engl J Med 1981;304:696-8.10. Natural history of intracranial aneurysms. N Engl J Med 1981;305:99.11. Intracranial aneurysm size and potential for rupture. J Neurosurg 1987;67:475-6.12. Wiebers DO, Torres VE. Screening for unruptured intracranial aneu-rysms in autosomal dominant polycystic kidney disease. N Engl J Med 1992;327:953-5.13. Forbes G, Fox AJ, Huston J III, Wiebers DO, Torner J. Interobserver variability in angiographic measurement and morphologic characterization of intracranial aneurysms: a report from the International Study of Un-ruptured Intracranial Aneurysms. AJNR Am J Neuroradiol 1996;17:1407-15.

14. Folstein MF, Folstein SE, McHugh PR. “Mini–Mental State”: a prac-tical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-98.15. Brandt J, Spencer M, Folstein M. The Telephone Interview for Cog-nitive Status. Neuropsychiatr Neuropsychol Behav Neurol 1988;1:111-7.16. Rankin J. Cerebral vascular accidents in patients over age 60. II. Prog-nosis. Scott Med J 1957;2:200-15.17. Juvela S, Porras M, Heiskanen O. Natural history of unruptured intra-cranial aneurysms: a long-term follow-up study. J Neurosurg 1993;79:174-82.18. Wirth FP, Laws ER Jr, Piepgras D, Scott RM. Surgical treatment of incidental intracranial aneurysms. Neurosurgery 1983;12:507-11.19. Nishimoto A, Ueta K, Onbe H, et al. Nationwide co-operative study of intracranial aneurysm surgery in Japan. Stroke 1985;16:48-52.20. Heiskanen O. Risks of surgery for unruptured intracranial aneurysms. J Neurosurg 1986;65:451-3.21. Rice BJ, Peerless SJ, Drake CG. Surgical treatment of unruptured aneurysms of the posterior circulation. J Neurosurg 1990;73:165-73.22. Jomin M, Lesoin F, Lozes G, Fawaz A, Villette L. Surgical prognosis of unruptured intracranial arterial aneurysms: report of 50 cases. Acta Neu-rochir (Wien) 1987;84:85-8.23. King JT Jr, Berlin JA, Flamm ES. Morbidity and mortality from elec-tive surgery for asymptomatic, unruptured, intracranial aneurysms: a meta-analysis. J Neurosurg 1994;81:837-42.


New England Journal of Medicine

CORRECTION

Unruptured Intracranial Aneurysms

To the Editor: The conclusions reached by Wiebers et al. (Dec. 10

issue)1 about the natural history of aneurysmal subarachnoid hemor-

rhage arouse concern because of the inhomogeneous grouping of pa-

tients and the differences in the rates of subarachnoid hemorrhage at

different sites. Since they included intracavernous aneurysms in their

determination of rupture rates, the rates for aneurysms truly within the

subarachnoid space may be underestimated, since intracavernous

aneurysms rarely cause subarachnoid hemorrhage.2 To a lesser ex-

tent, the same caveat may apply to proximal infraclinoid ophthalmic

aneurysms and those arising from the clinoidal segment of the carotid

artery, since they are often protected by dura and bone. The grouping

of aneurysms in these locations with aneurysms that are free within

the subarachnoid space combines categories of aneurysms that en-

tail very different risks of hemorrhage. Of the 1937 aneurysms, 669

(34.5 percent) were in these proximal locations, a point that may have

important implications for the overall findings (Table 1).

From the data provided, we cannot determine the effect of this dis-

tribution of aneurysms on the much higher (by a factor of 11) risk of

subarachnoid hemorrhage among the patients in group 2. Certainly,

the difference of 15 percentage points between the two groups in the

proportion of aneurysms free in the subarachnoid space may account

for some of the results. The data shown in Table 1 of the article by

Wiebers et al. suggest that the incidence of single aneurysms was

the same in the two groups. Since patients in group 2 had had a

previous subarachnoid hemorrhage that had been treated, they rep-

resent a population with a higher rate of multiple aneurysms and are

not comparable to the patients in group 1. This factor may also have

contributed to the difference in the natural history of unruptured in-

tracranial aneurysms between the groups and must be acknowledged

in any discussion of the natural history.

Another concern of ours is the relation between subarachnoid hem-

orrhage and the size of the aneurysm. Although Wiebers et al.3 have

written about the absence of subarachnoid hemorrhage in patients

with aneurysms that are less than 10 mm in diameter, many large

series have shown that the mean diameter of aneurysms in patients

who present with subarachnoid hemorrhage is less than 10 mm, as

noted by Dr. Caplan in his editorial.4 Therefore, we conclude that

there is little assurance that an aneurysm that is less than 10 mm will

not bleed.

We believe that the conclusions of this article should be modified to re-

flect a higher risk of subarachnoid hemorrhage at certain sites, since

this will affect the manner in which treatment options are presented to

patients.

Table 1. Distribution of Aneurysms.

Alejandro Berenstein, M.D.

Eugene S. Flamm, M.D.

Mark J. Kupersmith, M.D.

Beth Israel Medical Center

New York, NY 10128

References

1. The International Study of Unruptured Intracranial Aneurysms In-

vestigators. Unruptured intracranial aneurysms – risk of rupture

and risks of surgical intervention. N Engl J Med 1998;339:1725-

1733.

2. Kupersmith MJ, Hurst R, Berenstein A, Choi IS, Jafar J, Ransohoff

J. The benign course of cavernous carotid artery aneurysms. J

Neurosurg 1992;77:690-693.

3. Wiebers DO, Whisnant JP, O’Fallon WM. The natural history of

unruptured intracranial aneurysms. N Engl J Med 1981;304:696-

698.

4. Caplan LR. Should intracranial aneurysms be treated before they

rupture? N Engl J Med 1998;339:1774-1775.

To the Editor: Although we were encouraged to see a report on the

important problem of unruptured intracranial aneurysms, we are con-

cerned that selection bias, especially in the retrospective cohort, may

have undermined the study’s findings and recommendations.

We were approached to participate in this study and include any pa-

tients with unruptured intracranial aneurysms who were being fol-

lowed. Although we had several such patients, we declined the

invitation because of our concern that the cohort would not be

representative of the overall population of patients with unruptured

aneurysms. For instance, the vast majority of patients with unrup-

tured aneurysms who are referred to our institution have already been

surgically treated, leaving only a small minority with aneurysms with a

N Engl J Med 1999;340:1439-a



low risk on the basis of the natural history, and these aneurysms were,

for example, heavily calcified, partly intracavernous, tiny and laterally

located, or in elderly patients with other medical problems. Unfortu-

nately, aneurysms such as these also often pose a greater surgical

risk, further complicating the issue of their inclusion in a study.

We think that the data reported confirm our concern about selection

bias. The cohort consisted of 1449 patients at 53 centers who were

given a diagnosis over a period of 21 years (1970 to 1991). All the

centers are regional referral institutions that would be expected, on

the basis of the volume at our institution, to see 60 to 80 patients

with newly diagnosed unruptured aneurysms annually. Assuming this

to be the case, outcome data would have been reported for only 1.3

patients per year (2 percent of all patients seen). Even if one assumes

the volume in the referral centers to be only 10 percent of this value,

the cohort would represent only 20 percent of the patients in these

centers, which is still too small a percentage to be representative of

the population at large.

Thus, although we applaud any plans for a true population-based as-

sessment and some type of randomized trial addressing this problem

and hope that this article will trigger enough controversy to see that

goal accomplished, we recall the initial impressions that carotid artery

disease was benign and not in need of treatment, which were re-

versed by definitive studies showing that intervention was appropriate

for patients who were properly identified. The same could apply to un-

ruptured aneurysms, which the study shows still have a case fatality

rate of 66 percent when they are left to bleed.

For those of us treating this disease, the identification of appropri-

ate surgical candidates, combined with more cost-effective screening,

probably offers the greatest hope, since ongoing efforts to prevent

early rebleeding, cure vasospasm, reverse severe brain damage, and

refine microsurgical and endovascular techniques are having little ef-

fect on overall morbidity due to this disease.

E. Sander Connolly, Jr., M.D.

J.P. Mohr, M.D.

Robert A. Solomon, M.D.

Columbia University

New York, NY 10032

To the Editor: The annual rupture rate reported by Wiebers et al. is

considerably lower than that reported in other respected studies.1,2

One study found that unruptured aneurysms smaller than 5 mm in

diameter that subsequently ruptured were larger after rupture.3 The

Aneurysmal Subarachnoid Hemorrhage Cooperative Study2 demon-

strated that 24 percent of ruptured aneurysms are 5 mm or less. Rup-

ture of aneurysms smaller than 10 mm is not uncommon in our prac-

tice. The low rate of rupture of small aneurysms reported by Wiebers

et al. is most likely explained by the fact that growth and rupture are

time-dependent. Follow-up was not long enough to allow the expan-

sion and rupture of aneurysms.

The rates of surgical morbidity and mortality were higher in this study

than in other series.4 There have been microneurosurgical advances

since 1970, when the retrospective component began. It would not

be accurate to use high complication rates when one is analyzing the

risks and benefits of the obliteration of aneurysms. We are sure that

the authors accept the seriousness of these lesions and the potential

for poor outcomes (a mortality rate of up to 50 percent after rupture).

In addition, in 42 of the 205 patients who died during the 7.5 years

of follow-up, death was caused by intracranial hemorrhage. Was this

due to the aneurysm? Were autopsy data available?

Patients in whom the aneurysm was manipulated within 30 days after

diagnosis were excluded. This cohort most likely represents younger

patients who have aneurysms with worrisome features that make the

decision to operate straightforward. If these assumptions are true, the

rate of surgical complications would be lower in this group. The num-

ber of such patients and the reasons for treatment are not reported.

The locations of the aneurysms in this study differ from those in previ-

ous studies and suggest that there may have been a location-specific

bias.5 There were 256 cavernous aneurysms. The likelihood of rup-

ture is low if the lesion is completely intracavernous. These lesions

account for 18 percent of aneurysms in the retrospective study, but

for only 6 percent of cases of subarachnoid hemorrhage.

To advise patients with unruptured aneurysms properly, three factors

require consideration: the size and location of the aneurysm and the

patient’s age. The study does not provide information regarding the

rates of surgical complications as a function of the location or the

size of the aneurysm or the patient’s age. Unfortunately, all patients

are combined into one group that reflects various microneurosurgical

techniques. This approach is very misleading. We hope that this re-

port will prompt further investigation into this important clinical issue.

Philip E. Stieg, Ph.D., M.D.

Robert Friedlander, M.D.

Brigham and Women’s Hospital

Boston, MA 02115

References

1. Juvela S, Porras M, Heiskanen O. Natural history of unruptured

intracranial aneurysms: a long-term follow-up study. J Neurosurg

1993;79:174-182.

2. Sahs AL, Nibbelink DW, Torner JC. Aneurysmal subarachnoid

hemorrhage: report of the Cooperative Study. Baltimore: Urban &

Schwarzenberg, 1981.

3. Yasui N, Magarisawa S, Suzuki A, Nishimura H, Okudera T, Abe T.

Subarachnoid hemorrhage caused by previously diagnosed, pre-

viously unruptured intracranial aneurysms: a retrospective analy-

sis of 25 cases. Neurosurgery 1996;39:1096-1100.

4. King JT Jr, Berlin JA, Flamm ES. Morbidity and mortality

from elective surgery for asymptomatic, unruptured, intracranial

N Engl J Med 1999;340:1439-a



aneurysms: a meta-analysis. J Neurosurg 1994;81:837-842.

5. McCormick WF. Vascular disorders of nervous tissue: anomalies,

malformations, and aneurysms. In: Bourne GH, ed. The structure

and function of nervous tissue. Vol. 3. Biochemistry and disease.

New York: Academic Press, 1969:537-95.

To the Editor: In his editorial, Dr. Caplan states that `̀ patients with

previously ruptured aneurysms had 11 times the rate of rupture of pa-

tients without prior hemorrhage.´́ As I interpret the data of Wiebers

et al., this excess is applicable only to the subgroup of patients with

aneurysms that were less than 10 mm in diameter. Among patients

with aneurysms that were 10 mm or more, the rates of rupture are

roughly similar in the group with prior hemorrhage and the group with-

out it.

Allan Brett, M.D.

University of South Carolina School of Medicine

Columbia, SC 29203

The authors reply:

To the Editor: Approximately half the patients with cavernous

aneurysms also had noncavernous unruptured aneurysms. Although

intracavernous aneurysms can cause subarachnoid hemorrhage,

most are protected from the subarachnoid space. Other internal

carotid aneurysms are not protected. The annual rates of rupture

are only slightly increased by the exclusion of patients with cavernous

aneurysms (Table 1); patients in group 2 who had small (<10 mm) un-

ruptured aneurysms remain approximately 10 times as likely to have

a subsequent rupture as patients with small aneurysms in group 1.

Currently, the numbers of patients are too small (only a total of 32

aneurysmal ruptures) to determine meaningful rupture rates in group

1 and group 2 according to the six different locations and two size cat-

egories (24 subgroups). The presence of multiple unruptured intracra-

nial aneurysms was not a predictor of future rupture independent of

the size and location of the largest unruptured aneurysm. Unruptured

aneurysms were more likely to rupture in patients in group 2, but this

risk does not appear to be related to the presence of multiple unrup-

tured intracranial aneurysms.

The concern about microneurosurgical advances that have occurred

since 1970 and the exclusion of patients who underwent surgery in

the first 30 days after diagnosis is not relevant, since operative mor-

bidity and mortality were assessed only in the patients in the prospec-

tive group, beginning in late 1991. The base-line characteristics of the

surgically treated patients and those who were not so treated were vir-

tually identical, with minor differences in the mean age and aneurys-

mal size only among patients in group 1, underscoring the lack of

consensus about the selection of patients with unruptured intracranial

aneurysms as candidates for surgery.

Comparison of our retrospective results with those of a 30-year study

(1965 to 1995) in Rochester, Minnesota, of a population-based sam-

ple of patients with intracranial aneurysms1 (and unpublished data)

yielded strikingly similar demographic characteristics, aneurysmal

characteristics, and associated medical conditions, suggesting that

our group (representing approximately 40 percent of patients with un-

ruptured aneurysms who were seen at participating centers) may be

representative of the general population. A randomized trial would

involve a much greater prospective selection bias than our study be-

cause many patients would refuse to participate.

Data on the natural history of unruptured intracranial aneurysms con-

firm the conclusion that judgments about the probability of the rupture

of such aneurysms cannot be extrapolated from data on patients with

ruptured aneurysms. It appears that most aneurysms that are going

to rupture do so when they form or soon afterward and that the critical

size in terms of rupture is smaller for aneurysms that rupture early.

In our cohort, the patient’s age significantly predicted operative mor-

bidity and mortality. The influences of the size and location of

aneurysms in this study are not yet clear because of insufficient num-

bers of patients; this is one of the central reasons that the study has

been extended to involve a total of 5500 patients.

Table 1. Mean Annual Rates of Confirmed Subarachnoid Hemor-

rhage.

David O. Wiebers, M.D.

David G. Piepgras, M.D.

John Huston III, M.D.

Mayo Clinic

Rochester, MN 55905

for the International Study of Unruptured Intracranial Aneurysms In-

vestigators

References

1. Menghini VV, Brown RD Jr, Sicks JD, O’Fallon WM, Wiebers DO.

The incidence and prevalence of intracranial saccular aneurysms

and hemorrhage in Olmsted County, Minnesota, 1965 to 1995.

Neurology 1998;51:405-411.

N Engl J Med 1999;340:1439-a



To the Editor: Dr. Brett is correct. Aneurysms that were less than 10

mm in diameter were 11 times as likely to rupture in patients who had

prior bleeding from other aneurysms as in patients without prior sub-

arachnoid hemorrhage. Aneurysms that were at least 10 mm had a

similar rate of rupture whether or not there had been prior subarach-

noid hemorrhage.

Louis R. Caplan, M.D.

Beth Israel Deaconess Medical Center

Boston, MA 02215

N Engl J Med 1999;340:1439-a



CORRECTION

Unruptured Intracranial Aneurysms — Risk ofRupture and Risks of Surgical Intervention

Unruptured Intracranial Aneurysms — Risk of Rupture and Risks of

Surgical Intervention . On page 1729, in Figure 2B, the curves were

mislabeled. The upper curve, with the square symbols, should have

been labeled `̀ 10–24 mm,´́ and the lower curve should have been

labeled `̀ <10 mm.´́

N Engl J Med 1999;340:744


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Unruptured Intracranial Aneurysms â€” Risk of Rupture and Risks of Surgical Intervention