RESEARCH—HUMAN—CLINICAL STUDIES

TOPIC RESEARCH—HUMAN—CLINICAL STUDIES

Analysis of Nonmodifiable Risk Factors for

Intracranial Aneurysm Rupture in a Large,
Retrospective Cohort
Peter S. Amenta, MD*
Sanjay Yadla, MD*
Peter G. Campbell, MD*
Mitchell G. Maltenfort, PhD*
Saugat Dey, MBBS‡
Sayantani Ghosh, MBBS‡
Muhammad S. Ali, MD*
Jack I. Jallo, MD, PhD*
Stavropoula I. Tjoumakaris,
MD*
L. Fernando Gonzalez, MD*
Aaron S. Dumont, MD*
Robert H. Rosenwasser, MD*
Pascal M. Jabbour, MD*
*Department of Neurological Surgery,
Thomas Jefferson University, Philadel-
phia, Pennsylvania; ‡Bankura Sammilani
Medical College, University of Calcutta,
Bankura, West Bengal, India
Correspondence:
Pascal Jabbour, MD,
Department of Neurological Surgery,
Thomas Jefferson University,
909 Walnut St, 2nd Floor,
BACKGROUND: The risk factors predictive of intracranial aneurysm rupture remain
incompletely defined.
OBJECTIVE: To examine the association between various nonmodifiable risk factors
and aneurysm rupture in a large cohort of patients evaluated at a single institution.
METHODS: A retrospective analysis of patients admitted to a cerebrovascular facility
between January 2006 and 2010 with a primary diagnosis of cerebral aneurysm.
Aneurysms were divided into 2 groups: unruptured or ruptured. The dome diameter,
aspect ratio (AR), location, sidedness, neck morphology, and multiplicity were entered
into a central database. A full model was constructed, and a systematic removal of the
least significant variables was performed in a sequential fashion until only those vari-
ables reaching significance remained.
RESULTS: We identified 2347 patients harboring 5134 individual aneurysms, of which
34.90% were ruptured and 65.09% were unruptured. On admission, 25.89% of aneur-
ysms with a dome diameter ,10 mm and 58.33% of aneurysms with a dome .10 mm
were ruptured (P , .001). Of aneurysms with an AR .1.6, 52.44% presented following
a rupture (P , .001). The highest incidence of rupture (69.21%) was observed in
aneurysms with an AR .1.6, dome diameter ,10 mm, and a deviated neck. Deviated
neck-type aneurysms had a significantly greater incidence of rupture than classical neck-
type aneurysms (P , .001).
CONCLUSION: An AR .1.6, dome diameter .10 mm, a deviated neck, and right-sid-
edness are independently associated with aneurysm rupture.
KEY WORDS: Aneurysm location, Aneurysm morphology, Aneurysm size, Aspect ratio, Neck-type, Subarachnoid
hemorrhage
Neurosurgery 70:693–701, 2012 DOI: 10.1227/NEU.0b013e3182354d68 www.neurosurgery-online.com

Philadelphia, PA 19107.
E-mail: pascal.jabbour@jefferson.edu
Received, January 18, 2011.
Accepted, August 9, 2011.
Published Online, September 1, 2011.
Copyright ª 2011 by the
Congress of Neurological Surgeons
A
neurysmal subarachnoid hemorrhage
(SAH) incidence remains stable in the
United States, affecting approximately
30000 individuals each year.1 However, it con-
tinues to have a devastating impact on affected
patients with a 50% to 60% 30-day mortality
rate, and less than 60% of survivors progressed to
functional independence.1-3 With improved
ABBREVIATIONS: AR, aspect ratio; CI, confidence
interval; CTA, computed tomographic angiogra-
phy; ICA, internal carotid artery; ISUIA, Interna-
tional Study of Unruptured Intracranial Aneurysms;
JHN, Jefferson Hospital for Neurosciences; MRA,
magnetic resonance angiography; PCA, posterior
cerebral artery; PCOM, posterior communicating
artery; SAH, subarachnoid hemorrhage
imaging quality and availability, family screening,
and broader surveillance the prevalence of unrup-
tured aneurysms has increased.4,5 Treatment of
unruptured aneurysms by coiling or clipping
carries an associated risk that must be weighed
against the risk of future rupture.6-8 Therefore,
accurate predictions of the natural history of
unruptured cerebral aneurysms are a key factor in
counseling patients for elective treatment.9,10
Large collaborative studies have been conducted
to clarify the natural history of unruptured ane-
urysms, including the International Study of
Unruptured Intracranial Aneurysms (ISUIA).
Although aneurysm size and location were inves-
tigated in the original ISUIA data and its follow-up
publication, other aspects of morphology were not
reported.11 Aneurysm size and location have since

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AMENTA ET AL
been substantiated as reliable predictors of rupture risk.5,7,8
Other investigators have studied morphological parameters such
as aspect ratio,12,13 height-width ratio,14 neck type,14,15 and inflow
angle.15,16 However, few studies have analyzed these factors
together in a single cohort.
The goal of the present article was to highlight nonmodifiable
risk factors related to the risk of aneurysmal rupture in a large
cohort of patients who presented to a single institution. We aimed
to determine whether these commonly cited variables were
associated with rupture on presentation when applied to a large
sample size. We do not intend this study to serve as a guideline for
clinical decision making, nor did we attempt to construct
a treatment algorithm based on our findings.
PATIENTS AND METHODS
Patients
A retrospective analysis was done of patients admitted to Jefferson
Hospital for Neurosciences (JHN), a high-volume tertiary cerebrovascular
facility, between January 2006 and January 2010 with a primary diagnosis
of cerebral aneurysm. The study protocol was approved by the
Institutional Review Board of Thomas Jefferson University prior to
commencement. Aneurysms were divided into 2 groups based on their
rupture status: unruptured or ruptured aneurysm. Patients with an
unruptured aneurysm were admitted for one or more of the following
reasons: aneurysm diagnosed on workup of headache, transient ischemic
attack, stroke, or seizure, incidental aneurysm found on imaging study
performed for separate pathology (head trauma, etc), signs and symptoms
of cranial nerve compression (ie, third nerve palsy), and sentinel headache
(worst headache of life without evidence of SAH on CT or lumbar
puncture). Because JHN is a large tertiary care cerebrovascular center,
a significant number of patients with incidental aneurysms were directly
admitted from outpatient neurology, internal medicine, and family
medicine practitioners. Patients with ruptured aneurysms were admitted
to JHN through the Jefferson emergency department or from outside
institutions without cerebrovascular capabilities.
Data of interest were collected by retrospective review of electronic
medical records, outpatient charts, and radiographic reports. Information
on age, sex, history of tobacco use, aneurysm dome diameter, aspect ratio
(AR), location, aneurysm sidedness (left vs right), neck morphology
(classical or deviated neck types), and multiplicity (the presence of more
than 1 aneurysm) was entered into a central database. A history of previous
SAH was not included in the analysis, because it had already been shown
to be associated with an increased risk of rupture of additional aneurysms.
Thus, to more effectively evaluate the contributions of the variables listed
above, patients with a history of SAH were excluded from the study.
Family history was not used in the analysis because the data were not
recorded for a significant number of patients.
Only patients with a radiographically confirmed diagnosis of cerebral
aneurysm by computed tomographic angiography (CTA), magnetic
resonance angiography (MRA), or digital subtraction angiography were
included. Aneurysms were not grouped based on the imaging modality by
which they were identified. As per our protocol, all patients admitted with
an aneurysmal SAH underwent digital subtraction angiography on the day
of or day after admission.
In patients with multiple aneurysms, selection of the aneurysm for
treatment was based on the blood pattern on CT, evaluation of aneurysm
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size, and morphologic characteristics felt to increase the risk of rupture (ie,
presence of excrescence). Statistical analysis was performed by using
individual aneurysm risk.
Statistical Analysis
A full model, including all study variables, was constructed from the
information in the database. Backward stepwise regression, with system-
atic removal of the least significant variables, was performed in a sequential
fashion until only those variables reaching significance remained.
Univariate analysis was conducted to assess statistical differences in
individual nonmodifiable risk factors (size, AR, location, neck type, and
multiplicity) between patients with ruptured and unruptured aneurysms
by the use of the Student t test. Parameters that had statistically significant
associations with rupture status by univariate analysis were then included
in multivariate regression to further assess interdependence. Smoking
status and age were also included in multivariate regression because they
have demonstrated strongly independent associations with risk of
aneurysm rupture in previous studies.17,18 A P value of less than .05
was considered statistically significant. Data were analyzed with the use
of JMP 7.0.2 statistical software (SAS Institute, Cary, North Carolina).
Nonmodifiable variables of aneurysm size, AR, location, and multiplicity
were evaluated with CTA, MRA, angiography, or a combination of
modalities. Only saccular aneurysms with a discrete dome and neck were
included in the analysis. Aneurysms were included in the study regardless of
whether or not they were associated with an arteriovenous malformation. (1)
Aneurysm size was analyzed as a dichotomous variable of greater than or less
than 10 mm. (2) AR was calculated as the maximum perpendicular height in
millimeters divided by the neck width in millimeters (Figure 1). AR was
analyzed as a dichotomous variable of greater or less than 1.6 based on the
contemporary literature that suggests that an AR of 1.6 is signifi-
cant.12,13,15 (3) Neck type was evaluated by CTA, MRA, or angiography
and aneurysms were classified as either having a classical (apical) or
deviated neck type (Figure 1). (4) Location was analyzed as a dichotomous
variable based on the parent vessel. Aneurysms of the anterior
communicating artery, anterior cerebral artery, posterior communicating
artery (PCOM), middle cerebral artery, cavernous or carotid-ophthalmic
segments of the internal carotid artery (ICA), and distal ICA or ICA
bifurcation were considered anterior circulation. Aneurysms of the basilar
artery, posterior cerebral artery (PCA), vertebral artery, and superior
cerebellar artery were considered posterior circulation. To address the
ISUIA inclusion of PCOM aneurysms in the posterior circulation, we
performed 2 separate analyses of ruptured and unruptured aneurysms in
which PCOM aneurysms were included in either the anterior or posterior
circulation. (5) Multiplicity was analyzed as a dichotomous variable of 1
aneurysm or more than 1 aneurysm at any site.
RESULTS
The database contained 2347 patients harboring 5139 in-
dividual aneurysms, for which complete information was available
for 5134 aneurysms. Of these aneurysms, 1792 (34.90%) were
ruptured and 3342 (65.09%) were unruptured. The distribution
of individual aneurysms and the number of ruptured and
unruptured aneurysms within each group are listed in the Table.
Of the aneurysms, 3587 (69.87%) arose from the left side of the
circulation, 1183 (32.98%) of which ruptured. There were 1547
(30.00%) right-sided aneurysms, 609 (39.37%) of which
ruptured. Six hundred twelve (28.43%) aneurysms demonstrated
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 ANEURYSMAL RUPTURE RISK FACTOR ANALYSIS

FIGURE 1. Calculation of AR and depiction of aneurysm neck types. A, the AR is calculated using the following equation: AR =
dome height (mm)/neck diameter (mm). B, aneurysms were classified as having either a classical or deviated neck type. AR, aspect
ratio.

a classical neck type, 174 (28.43%) of which were ruptured; 4526
(88.16%) aneurysms had a deviated neck, 1619 (35.77%) of
which were ruptured.
The size of the aneurysm dome was also evaluated in both the
ruptured and unruptured groups: 3056, 580 (25.89%) of which
were ruptured, were found to have domes measuring , 10 mm;
2078 aneurysms possessed domes .10 mm, and of these, 1212
(58.33%) were ruptured on admission (P , .001). Aneurysm AR
was analyzed as a dichotomous variable of greater or less than 1.6.
Of the aneurysms, 2374 (46.24%) were calculated to have an AR
,1.6, whereas 2760 (53.76%) of the aneurysms had an AR
.1.6. Of aneurysms with an AR ,1.6, 19.82% were ruptured,
and 52.44% of aneurysms with an AR .1.6 presented following
a rupture (P , .001). Six hundred twelve aneurysms were
classified as having a classical neck type and 174 (28.43%) of
these were ruptured, and 4526 aneurysms had a deviated neck
type and 1619 (35.77%) of these were ruptured (P , .001).
The combination of AR, dome size, and neck type within an
individual aneurysm was also investigated (Figure 2). One
thousand two hundred seventy aneurysms were found to have
an AR .1.6, a dome diameter .10 mm, and a deviated neck
type; 879 (69.21%) of these aneurysms were ruptured on
admission. Two hundred thirty aneurysms had an AR .1.6,
a dome diameter .10 mm, and a classical neck type, of which
128 (55.65%) ruptured. 224 (30.43%) of 736 aneurysms had an
AR .1.6, dome diameter ,10 mm, and a deviated neck type.
One hundred thirty-eight aneurysms had an AR .1.6, dome
diameter ,10 mm, and a classical neck type, of which 14
(10.14%) ruptured. Five hundred two aneurysms had an AR
,1.6, dome diameter .10 mm, and a deviated neck type; 192
(38.25%) of these aneurysms were ruptured. Seventy-six
aneurysms demonstrated an AR ,1.6, dome diameter .10
mm, and a classical neck type, of which 13 (17.11%) ruptured.
Two thousand fifteen aneurysms had an AR ,1.6, dome

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AMENTA ET AL

posterior circulation aneurysms. When PCOM aneurysms were

TABLE. 5138 Aneurysms by Location and Rupture Status on classified as arising from the anterior circulation, 4737 (92.19%)
Admissiona of the total number of aneurysms arose within the anterior
Aneurysm circulation, 35.28% of which were ruptured. Four hundred one
Location Ruptured Unruptured Total % Ruptured SE (7.80%) aneurysms were found in the posterior circulation, and
Cavernous 159 407 566 28.09 1.89%
30.42% of these aneurysms were ruptured. If PCOM aneurysms
ICA/CO were considered along with posterior circulation aneurysms, 3684
ICA 114 297 411 27.74 2.21% (71.70%) aneurysms arose from the anterior circulation, 1247
ACOM/ACA 485 969 1454 33.36 1.24% (33.85%) of which were ruptured; 1454 posterior circulation
MCA 489 764 1253 39.03 1.38% aneurysms were found with 546 (37.55%) ruptured.
Basilar 94 207 301 31.23 2.67% Dome diameter .10 mm, AR .1.6, and right sidedness had
PCOM 424 629 1053 40.27 1.51%
statistically significant associations with rupture status in
PCA/SCA 28 72 100 28.00 4.49%
Total 1793 3345 5138
univariate analysis. Aneurysm size of .10 mm had an odds
ratio (OR) of 5.97 for rupture (95% confidence interval [CI],
a
ACA, anterior cerebral artery; ACOM, anterior communicating artery; CO, carotid- 5.27-6.77; P , .001). AR .1.6 had an OR of 4.46 for rupture
ophthalmic; ICA, internal carotid artery; MCA, middle cerebral artery; PCA, (95% CI, 3.94-5.05; P , .001). Presence of a deviated neck type
posterior cerebral artery; PCOM, posterior communicating artery; SCA, superior
cerebellar artery; SE, standard error.
had an OR of 1.40 for rupture (95% CI, 1.17-1.69; P = .001),
and aneurysms of the anterior circulation had an OR of 0.85 for
rupture (95% CI, 0.75-0.97; P = .012).
diameter ,10 mm, and a deviated neck type; 323 (16.03%) of In multivariate analysis, dome diameter .10 mm and an AR
these aneurysms were ruptured on admission. Finally, 167 .1.6 remained statistically significant. The presence of a deviated
aneurysms had an AR ,1.6, dome diameter , \10 mm, and neck type became statistically significant in multivariate analysis,
a classical neck-type; 19 (11.38%) of these aneurysms ruptured. whereas right sidedness was no longer significant. Dome diameter
Two separate analyses of the incidence of ruptured and .10 mm had an OR of 4.35 for rupture (95% CI, 3.79-4.99;
unruptured aneurysms within the study population were per- P , .001). AR .1.6 had an OR of 2.81 for rupture (95% CI,
formed with PCOM aneurysms included as either anterior or 2.45-3.22; P , .001). Presence of a deviated neck had an OR of
2.11 for rupture (95% CI, 1.72-2.59; P , .001) and aneurysms
of the anterior circulation had an OR of 0.77 for rupture (95%
CI, 0.67-0.89; P = .001). Right sidedness had an OR of 1.32 for
rupture (95% CI, 1.15-1.52; P = .001). PCOM aneurysms were
considered anterior circulation aneurysms for the multivariate
analyses.

DISCUSSION
Intracranial aneurysms, which are found in approximately 2%
to 5% of the population, represent a class of relatively common
vascular lesions. Despite their prevalence, only 1% to 2% of
aneurysms will rupture, resulting in SAH.19-21 Through retro-
spective review, the present study evaluates associations between
several morphological risk factors and the occurrence of
aneurysmal rupture.

FIGURE 2. Number of ruptured and unruptured aneurysms based on the si-
multaneous evaluation of AR, dome diameter, and neck type in an individual
aneurysm. AR was analyzed as a dichotomous variable of greater or less than 1.6.
Dome diameter was analyzed as a dichotomous variable of greater than or less than
10 mm. Neck type was analyzed as a dichotomous variable: classical vs deviated
neck type. The highest incidence of rupture was found in aneurysms with an AR
.1.6, dome diameter .10 mm, and a deviated neck type. Small aneurysms (AR
,1.6, dome diameter ,10) were the most frequently encountered aneurysms
within the series. Small aneurysms with a classical neck type had the lowest
incidence of rupture. AR, aspect ratio.
Aneurysm Size
The present study was not designed in a manner conducive to
establishing a threshold value or "critical size" predictive of
rupture. We did find that aneurysms with a dome diameter .10
mm are significantly more likely to present following a rupture in
comparison with aneurysms measuring ,10 mm. Of those
aneurysms ,10 mm in diameter, 25.89% were ruptured,
whereas 58.33% of aneurysms .10 mm had ruptured before
admission. Thus, our results are similar to the data presented in
the original ISUIA report, in which aneurysms with a dome
diameter $10 mm were at a higher risk of rupture.22 Perhaps,

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more importantly, within our series, over one quarter of
aneurysms ,10 mm were ruptured on admission, thereby
supporting the existing literature that demonstrates that smaller
aneurysms rupture frequently. Juvela et al19 provided some of the
most convincing data in their experience with 142 patients
harboring unruptured aneurysms over 2575 person-years in
a patient population not offered surgical intervention. The key
data was that an aneurysmal dome ,6 mm in diameter was found
in 23 (70%) of 33 ruptured aneurysms that had been initially
followed in the wake of a previous diagnosis. Perhaps, of even
greater importance, is the observation that, in 3 patients with
aneurysms ,5 mm, aneurysmal diameter increased significantly
before rupture. A thorough review of the literature will reveal
multiple studies reporting a significant rupture rate in aneurysms
,5 mm in diameter.23,24
Our results do not clarify the debate over the aneurysm size at
which the risk of rupture is the greatest. If nothing else, however,
they do reinforce what is commonly encountered in practice.
Larger aneurysms appear to rupture with a significantly greater
frequency than smaller aneurysms. Importantly, smaller aneur-
ysms continue to pose a significant challenge in the management
algorithm, because they were also found to be ruptured in
a significant percentage of cases.25-27
Aspect Ratio
Using animal models of aneurysmal blood flow, Ujiie et al28
published the morphometric and hemodynamic data pertaining
to the use of the AR as a clinically relevant variable. Intra-
aneurysmal flow correlates with the AR and decreases as the
aneurysmal neck narrows and dome volume (dome height)
increases. In clinical retrospective analyses, the AR threshold
value was established as 1.6, because nearly 80% of ruptured
aneurysms demonstrated an AR .1.6. Conversely, approxi-
mately 90% of unruptured aneurysms displayed an AR ,1.6.13
The AR was analyzed as a dichotomous variable of greater or less
than 1.6 based on these findings.12,13,15 We found that 46.24% of
aneurysms within our series had an AR ,1.6, whereas 53.76% of
aneurysms had an AR .1.6. The rates of rupture were somewhat
different than those published by Ujiie et al,28 with 19.82% of
aneurysms with an AR ,1.6 rupturing and 52.44% of aneurysms
with an AR .1.6 presenting after a rupture. Of unruptured
aneurysms, 66.22% had an AR ,1.6, whereas 33.78% of
unruptured aneurysms had an AR .1.6. Thus, our data support
the association between higher ARs and an increased incidence of
rupture. Importantly, our data demonstrate that aneurysms with
an AR ,1.6 rupture frequently, and suggest that this value is not
a clinically useful threshold.5,29,30
To clarify the importance of the AR, we performed a multivariate
analysis in which the incidence of aneurysm rupture was determined
for individual aneurysms with a specific combination of AR, dome
diameter, and neck type. We found that 1270 aneurysms had an AR
.1.6, dome diameter .10 mm, and a deviated neck type. Of
these aneurysms, 879 (69.21%) were ruptured on presentation.
This value was significantly higher than the 38.25% of ruptured
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ANEURYSMAL RUPTURE RISK FACTOR ANALYSIS
aneurysms with an AR ,1.6, dome diameter .10 mm, and
a deviated neck type. The predictive value of the AR combined
with dome diameter and neck type held true for small aneurysms,
as well. In aneurysms with a dome diameter ,10 mm and
a deviated neck, the incidence of rupture was 30.43% for
aneurysms with an AR .1.6 and 16.03% when the AR was
,1.6. In classical neck-type aneurysms, an AR .1.6 was also
associated with a significantly greater incidence of rupture in
aneurysms with a dome diameter .10 mm. Aneurysms with
a dome diameter ,10 mm and a classical neck showed no
significant difference in rupture rate regardless of the AR.
Furthermore, the combination of AR, aneurysm dome di-
ameter, and neck type held a significantly stronger predictive value
than any variable considered alone. Thus, these data draw
attention to the need for further prospective analysis to further
define the AR threshold value and to investigate the significance of
AR within the context of other morphologic variables.
Aneurysm Location
Anterior circulation aneurysms were found to be ruptured with
incidences ranging from 27.74% to 40.27%. PCOM aneurysms
demonstrated the highest incidence of rupture (40.27%). Poste-
rior circulation aneurysms, basilar artery and PCA or superior
cerebellar artery, had incidences of rupture of 31.23% and
28.00%, respectively, which fell within the range of anterior
circulation aneurysms. As a result, our findings do not agree with
the existing literature, in which posterior circulation aneurysms
exhibit a greater risk of rupture.22,25
The findings of the ISUIA retrospective review have been
criticized for the inclusion of PCOM aneurysms within the
posterior circulation. The data showed basilar tip, PCOM,
vertebrobasilar, and PCA aneurysms to display a higher risk of
rupture in group 1 patients, while the basilar tip was the only
location predictive of rupture in group 2.22 To address the
importance of the inclusion of PCOM aneurysms within the
anterior or posterior circulation, we performed 2 separate
analyses. When PCOM aneurysms were included in the anterior
circulation, 4737 (92.19%) of the total number of aneurysms
arose within the anterior circulation, 35.28% of which were
ruptured; 401 (7.80%) aneurysms were found in the posterior
circulation, and 30.42% of these aneurysms were ruptured.
If PCOM aneurysms were considered along with posterior
circulation aneurysms, 3684 (71.70%) aneurysms arose from the
anterior circulation, 1247 (33.85%) of which were ruptured. One
thousand four hundred fifty-four posterior circulation aneurysms
were found with a 37.55% incidence of rupture. Thus, the
inclusion of PCOM aneurysms in the posterior circulation group
significantly influenced our results. Because PCOM aneurysms
demonstrated the highest incidence of rupture among all
locations, their inclusion in the anterior circulation resulted in
a significantly greater incidence of rupture for these aneurysms
compared with the posterior circulation. Furthermore, when
considered as part of the posterior circulation, the incidence of
rupture for this group was significantly greater compared with
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AMENTA ET AL
anterior circulation aneurysms. Also, the incidence of posterior
circulation rupture was significantly higher between analyses
when PCOM aneurysms were classified as arising from the
posterior circulation. As a result, our data support the criticism
that has befallen the ISUIA data for inclusion of PCOM
aneurysms within the posterior circulation cohort. The present
study suggests that the choice to include PCOM aneurysms in the
posterior circulation cohort potentially falsely elevates the in-
cidence of rupture for posterior circulation aneurysms. Regardless
of the classification of PCOM aneurysms, the anterior circulation
incidence of rupture did not differ significantly, perhaps because
of the significantly greater number of aneurysms present in the
anterior circulation.
Although aneurysm sidedness represents a variable that is far less
examined, we found a significant difference in the incidence of
rupture between sides. Six hundred nine of the 1547 (39.37%)
right-sided aneurysms were ruptured, whereas 1183 of the 3587
(32.98%) left-sided aneurysms ruptured. The significantly greater
incidence of rupture in right-sided aneurysms is not consistent
with other reports within the literature.31 Because we do not have
a pathophysiologic explanation for the increased number of
ruptured right-sided aneurysms, we have to acknowledge the
potential existence of a chance finding or a process that has yet to
be adequately described. Regardless of the underlying cause,
aneurysm sidedness is a variable in obvious need of further
investigation.
Neck Type
When evaluating the morphology of the aneurysmal neck,
a distinction is made between aneurysms that arise from the parent
artery midline (classical neck type) and those whose neck is
deviated (deviated neck type) in the direction of one of the
daughter arteries.29 We must point out that the accurate analysis
of neck type in a large retrospective series such as this is difficult
and open to significant inter- and intraobserver variability. Neck
type was assigned by the attending physician managing each
individual patient and the determination was not blinded. The
assignation of neck type to a particular aneurysm was not
discussed among physicians, nor was there a consensus in the
morphologic criteria needed to classify an aneurysm as having
a classical or deviated neck type. Nevertheless, a significantly
greater percentage of aneurysms with a deviated neck type,
35.77%, were ruptured compared with the 28.43% of ruptured
classical neck-type aneurysms. This finding is consistent with
data from studies within the literature.32-34 Future computational
and clinical analyses are needed to better define the risk of rupture
in relation to neck type.
Limitations of the Present Study
The present study is limited by its retrospective design and the
relatively short follow-up period of 4 years. A longer period of
observation of unruptured aneurysms is necessary to estimate the
lifetime risk of rupture, and there is no way to know if treated
unruptured aneurysms would have ever ruptured in the future. As
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a result, the data pertaining to unruptured aneurysms may not
reflect the lifetime risk of rupture to this population.
The article would have gained significant strength if the
variables had been evaluated in a continuous manner. This
approach would have allowed for the identification of ideal
threshold values for dome diameter and AR beyond which the
incidence of rupture was significantly increased. The data had been
entered in a dichotomous fashion from the initiation of the study,
and specific characteristics beyond what is presented are not
available.
Unruptured aneurysms were admitted for a variety of reasons,
ranging from incidental findings to sentinel headache, thereby
introducing a significant selection bias. Furthermore, patients
presented with a varying number of medical comorbidities that
influenced the decision-making process in a significant number of
patients. The study reflects the practice patterns of multiple
physicians, each with unique training, comfort level, and man-
agement style. Additionally, because JHN is a high-volume tertiary
care cerebrovascular facility, a large number of patients are directly
admitted with the preconceived notion that their aneurysm
requires immediate treatment. Despite counseling and the offer
to observe a percentage of aneurysms, patients often demand
treatment. As a result, the decision to treat a particular unruptured
aneurysm was influenced by multiple factors not included in our
analysis.
Finally, although the size of the series gives the study its greatest
strength, certain important characteristics, such as family history
of SAH, were not available for a percentage of patients. Future
prospective investigations should attempt to include all of these
variables in their analyses.
CONCLUSION
To our knowledge, we have presented data from one of the
largest retrospective reviews of ruptured and unruptured aneur-
ysms. Dome diameter .10 mm and an AR .1.6 were associated
with the highest incidence of rupture. Furthermore, simultaneous
consideration of both variables along with neck type held
a considerably higher predictive value than the use of any
variable in isolation. The inclusion of PCOM aneurysms within
the anterior or posterior circulation significantly influenced the
incidences of rupture for each group. Right-sided aneurysms
ruptured more frequently than left-sided aneurysms, while
a significantly higher incidence of ruptured deviated neck-type
aneurysms was found compared with classical neck-type
aneurysms.
The methodology used imposes significant restrictions on the
interpretation of the results, because selection bias and practice
patterns affect the final outcomes. As a result, this study cannot be
used as a basis on which to guide clinical decision making.
Nevertheless, the evaluation of commonly cited risk factors in such
a large patient population was able to lend additional insight into
the characteristics of ruptured and unruptured aneurysms upon
initial presentation. Additional prospective analysis of these
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morphologic variables combined with extended follow-up of
unruptured aneurysms is needed to better define the characteristics
predictive of rupture.
Disclosure
The authors report no disclosures of funding, personal conflicts of interest, or
financial interests pertaining to this article.
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COMMENTS
A
uthors examined the associations between various nonmodifiable
risk factors and admissions at Jefferson Hospital for Neurosciences
for ruptured (RAs) or unruptured intracranial aneurysms (UAs).
There are multiple difficulties in interpreting the results of this type of
study. Sources of biases are so numerous and complex that exploring and
discussing them all would be longer than the original article.
To start, 1 set of problems is related to the multiplicity of lesions: Surely
among the 1792 patients with RAs, some patients with nonlocalizing
subarachnoid hemorrhages and 2 or more aneurysms were treated by
coiling. The treating team would commonly assume that the larger
aneurysm was responsible for the bleed. This unproven assumption would
then be encrypted into the database. It would be no wonder if, at the end,
the results of the study would point at ruptures being more common in
larger than smaller lesions. This, of course, is begging the question.
Another set of problems is related to the comparison that is being made.
Admission for RAs is taken as a surrogate for UAs that have now shown
their propensity to rupture. On the other hand, some UAs are presumably
unruptured only for the time of diagnosis; for all we know, UAs could be
a mixture of some nonrisky, some “yet-to-rupture” lesions sharing all
“nonmodifiable risk factors” with RAs. But how long should UAs be
observed to qualify as low-risk lesions, to be distinguished from high-risk
lesions, according to their characteristics? Status on admission cannot
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AMENTA ET AL
represent a meaningful observation period. This only shows that a natural
history of aneurysms cannot come out of a comparison between
admissions for RAs and UAs.
A thought experiment may help illustrate another, most important
problem with this type of material: selection bias. Let us imagine that
during the period of data collection (2006-2010), clinicians followed the
implicit advice from the ISUIA study published in 19991: the natural
history of unruptured aneurysms smaller than 10 mm is so benign that
nothing should be offered, and no patient should be admitted for
asymptomatic aneurysms 10 mm or less. In this work, 1212 of 1792
ruptured aneurysms (68%, already a high proportion, perhaps reflecting
referral bias) are larger than 10 mm, but 100% of patients admitted for
unruptured aneurysms now have lesions larger than 10 mm. The
methodology used in this article would show that the smaller the
aneurysm, the larger the risks of rupture. This implausible thought
experiment only shows that even if the data are prospectively collected,
this methodology can never disentangle true risk factors from
confounders such as referral and selection biases, since we are not
looking at UAs, we are looking at UAs admitted to Jefferson.
One general, insurmountable problem is the hope to find a “natural
history” of an incidental imaging finding, nearly a contradiction in terms,
since the finding is by definition irrelevant to the disease. The data that
are being collected are only a reflection of the availability and use of
imaging equipment, of comorbidities that led to diagnostic testing. We
can imagine UAs having a much different “natural history,” according to
this research methodology, in places where imaging is not so widely
available. We only have to remember the times when noninvasive
imaging did not exist, when less than 20% of aneurysms were
unruptured on admission, to realize that the natural history of an
imaging finding is nothing but the history of medical imaging, of its use
and abuse.2
Prospective longitudinal cohort studies would be needed to avoid some
of the aforementioned problems, but many would remain. Cohort studies
such as ISUIA end up comparing risks of treatment in patients we feel
must be treated with the supposed natural history of patients we do not
want to treat, surely an invalid procedure, no matter how much we toil
with statistical adjustments.2
How then, have we become convinced that a “natural history of UAs”
would be needed, and that statistical methods could distinguish what is
natural, what is man made in this story? The fatal logical fallacy
underlying all observational studies is the, at first sight, plausible but, on
further reflection, false premise that an “accurate prediction of the
natural history of UAs” is needed to be “weighted against risks of
treatments,” as the authors pretend. How are we supposed to do that?
The only way to make sense of comparing immediate risks of treatments
with long-term risks of a disease is through Markov modeling, in fact,
computerized speculations that assume the facts that need to be
proved.3,4 The so-called natural history of UAs more often serves to
instill fear to justify risky preventive interventions than to provide a “key
factor in counseling patients for elective treatment,” as the authors claim
in the introduction.
It seems to us that we have replaced self-promoting case series with
pseudo-scientific retrospective studies that now use sophisticated statis-
tical methodologies. The problem is that, inserted between the in-
troduction and the results sections, “Methods” have become like black
boxes that readers, reviewers, and, we suspect, sometimes authors
themselves, understand barely enough to identify intrinsic pitfalls and
biases. While we can pause a minute to muse about a science-fiction story
in which you could guess someone’s hometown by the presence of
700 | VOLUME 70 | NUMBER 3 | MARCH 2012
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Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.
a right-sided craniotomy (right sidedness being in this article a risk
factor), that some people may use results of this study to justify treatment
decisions is a serious matter.
Epidemiological methods are not appropriate for clinicians hoping to
justify their clinical decisions.5 Patients are not exposed to medical
interventions the way populations are exposed to mercury. Can clinicians
act first and ask questions, do the research, later? By then it is too late to
protect patients from unjustified decisions and unproved interventions,
and it is too late for sound and ethical research; patients have not
consented to research, but to care that was supposedly informed and
based on reliable knowledge. The appropriate way for clinicians to deal
with clinical dilemmas is not to pretend we know and to act, to later
admit the uncertain, and do the biased research without the consent of
participants. The only way to justify decisions that involve risky
preventive treatments in asymptomatic individuals is to show, using
randomized allocation of treatment options, that treatments are safe and
effective, and above all, that they do more good than harm, in the same
patients. We cannot expect scientific methods to realize their normative,
truth-seeking potential role in regulating medical actions, or to protect
patients from error, bias, and abuse, when the science is only introduced
after the fact. In the mean time, waiting for the results of trials, statistical
methods applied to past admissions for an imaging finding cannot justify
past actions and cannot guide future clinical decisions, without grave
dangers. Clinicians must get their acts together and propose inter-
ventions that have yet to be shown beneficial only within the context of
appropriate trials.
Jean Raymond
Marc Kotowski
Tim E. Darsaut
Montreal, Quebec, Canada
1. The International Study of Unruptured Intracranial Aneurysms Investigators.
Unruptured Intracranial Aneurysms? Risk of Rupture and Risks of Surgical
Intervention. N Engl J Med. 1998;339:1725-1733.
2. Raymond J. Incidental intracranial aneurysms: rationale for treatment. Curr Opin
Neurol. 2009;22(1):96-102; Review.
3. Greving JP, Rinkel GJ, Buskens E, Algra A. Cost-effectiveness of preventive
treatment of intracranial aneurysms: new data and uncertainties. Neurology. 2009;73
(4):258-265.
4. Raymond J, Molyneux AJ, Takao H, Nojo T, Ohtomo K. Unruptured intracranial
aneurysms: evidence and speculations. Radiology. 2008;247(1):294. author reply
294.
5. Byar DP. Problems with using observational databases to compare treatments. Stat
Med. 1991;10:663-666.
6. Raymond J, Darsaut TE, Molyneux AJ. A trial on unruptured intracranial
aneurysms (the TEAM trial): results, lessons from a failure and the necessity for
clinical care trials. Trials. 2011;12(1):64.
T he authors provide an analysis of nonmodifiable risk factors for rupture
of intracranial aneurysms in a large, retrospective cohort. As the authors
point out, an understanding of these risk factors is critical in understanding
the natural history of unruptured intracranial aneurysms and will ultimately
aid in decision making, as an increasing number of incidental aneurysms are
being discovered. The authors confirm a number of nonmodifiable risk
factors, namely an aspect ratio of greater than 1.6, dome size greater than 10
mm, and a deviated neck as being independently associated with aneurysm
rupture. Although not terribly novel, the study does confirm these pre-
viously noted morphometric characteristics in a large patient cohort. Ulti-
mately, however, the retrospective study design does not allow for detailed
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 ANEURYSMAL RUPTURE RISK FACTOR ANALYSIS

analysis of the natural history of unruptured aneurysms, a point which
significantly weakens the conclusions of the article. The quality of these
studies relies on comprehensive and adjudicated data collection, and this
study lacks critical information regarding the reason for admission in
patients with an unruptured aneurysm, as well as data regarding treatment
decisions. This paves the way for substantial selection bias, which is com-
mon in this type of study. Although this study does not ultimately help in
decision making regarding treatment of unruptured intracranial aneurysms,
it does provide evidence that further supports the notion that morphological
characteristics of intracranial aneurysms are associated with risk of rupture.
Additional longitudinal, prospective patient studies that include advanced
neuroimaging and analytic software will be needed to provide a deeper
understanding of if and when an unruptured aneurysm may rupture.
Brad Zacharia
New York, New York

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