From the Department of Neurology, Academic Hospital Utrecht (T.W.M.R.,
G.J.E.R., A.A.), and the Julius Center for Patient Oriented Research (A.A.),
University of Utrecht; and the Department of Neurology, Academic Medical
Center (M.L.), Amsterdam, the Netherlands.
Correspondence to Dianne Raaymakers, MD, University Department of Neurology, Heidelberglaan 100, 3584 CX Utrecht, Netherlands. E-mail t.w.m.raaymakers{at}neuro.azu.nl
Methods—Through Medline and additional searches by hand,
we retrieved studies on clipping of unruptured (additional,
symptomatic, or incidental) aneurysms published
from 1966 through June 1996. Two authors independently extracted data.
We used weighted linear regression for data analysis.
Results—We included 61 studies that involved 2460 patients (57%
female; mean age, 50 years) and at least 2568 unruptured
aneurysms (27% >25 mm, 30% located in the posterior
circulation). Mortality was 2.6% (95% confidence interval [CI],
2.0% to 3.3%). Permanent morbidity occurred in 10.9% (95% CI, 9.6%
to 12.2%) of patients. Postoperative mortality was significantly lower
in more recent years for nongiant aneurysms and
aneurysms with an anterior location; the last 2 characteristics
were also associated with a significantly lower morbidity.
Conclusions—In studies published between 1966 and 1996 on
clipping of unruptured aneurysms, mortality was 2.6% and
morbidity was 10.9%. In calculating the pros and cons of preventive
surgery, these proportions should be taken into account.
Advising an individual patient about whether or not to undergo surgery
for an unruptured aneurysm represents a clinical
dilemma. Adequately balancing benefits and risks requires reliable data
on surgical outcome. Results of treatment used in previous decision
analyses on this subject3 4 5 6 7 are based on
relatively few studies. We therefore performed an extensive
meta-analysis on the mortality and morbidity of surgery for
unruptured intracranial aneurysms.
Search Strategy
Data Extraction
In case of disagreement between the 2 readers, consensus was reached by
joint review of the study. For the translated studies, we relied on
data extraction by the translator only.
Data Analysis
After we consulted the original authors, a large study with >700
patients was excluded because <90% of aneurysms had been
clipped.72
Study Characteristics
Patient Characteristics
Aneurysm Characteristics
Effectiveness of Operation
Postoperative Mortality
In the univariate weighted linear regression
analysis (Table 1
In the multivariate weighted linear regression
analysis (Table 2
Postoperative Morbidity
In univariate weighted linear regression analysis
(Table 1
In multivariate weighted linear regression
analysis (Table 2
Subgroup Analysis of Studies of Good Quality
The data extraction from the parent publications had several
limitations. We had to rely on mortality and morbidity data as provided
by the authors, who were often the neurosurgeons who had performed the
operations. This may have led to underestimation of surgical
complications.73 Adequate descriptions of outcome
measures were often lacking, and assessment of neuropsychological
function or quality of life was not performed in any of the studies.
Duration of follow-up was not specified in most studies. Only very few
publications provided data on effectiveness of clipping; hence, no
reliable figures could be presented for this item.
We included a large number of studies that had variable patient
inclusion criteria, definitions of outcome, length of follow-up, and
collection of other variables of interest. This variability affects
the interpretation of the results of our meta-analysis. Pending
more prospective, well-designed studies, our study analyzed the
best available evidence that can be used to make treatment decisions.
The subgroup analysis for studies that fulfilled criteria of
good quality showed mortality figures, which were essentially the same
for the complete group of 61 studies; the morbidity percentages tended
to be somewhat higher (although not significant) in the studies of high
quality (12.7%) compared with the overall percentage (10.9%). This
finding supports the consistency of our results.
We found mortality and morbidity rates to be much higher than those
used in previous decision analyses on surgery for unruptured
intracranial aneurysms.3 4 5 6 7 These
decision analyses estimated baseline cumulative surgical
mortality plus morbidity at 4% to 6.5%. The higher rates for
mortality and morbidity in our study indicate that advice on whether or
not to proceed with surgery will change toward a more conservative
attitude in many cases.
We included studies published from 1966 onward in this
meta-analysis, although postoperative mortality and morbidity
might be less now than 3 decades ago. Indeed, in univariate
analysis, mortality decreased in more recent years. For
postoperative morbidity, however, no time trend was found. In 5 of the
6 studies published before 1977, probably no operation microscope was
used; if we exclude these studies from the analysis,
postoperative mortality and morbidity were similar to those of the
complete group of studies. We conclude that aneurysm
characteristics, particularly aneurysm size, are much more
important prognostic factors for outcome than year of publication.
The coefficients we found in multivariate
analyses allow a rough estimate of mortality and morbidity for
specific groups of patients (see Appendix
We used rather broad categories to describe aneurysm size:
<10 mm, between 10 and 25 mm, and
The proportion of giant aneurysms and aneurysms in the
posterior circulation in our meta-analysis is relatively high.
This may cause an overestimation of mortality and morbidity. The
percentage of symptomatic unruptured aneurysms was
also high, which might be attributed to the rather broad definitions of
the original authors, since aneurysms in patients investigated
for headache or dizziness were often considered
"symptomatic."
A Medline search for randomized clinical trials retrieves only about
50% of relevant studies74 ; the yield for
observational studies has not been studied yet but might be even lower.
We therefore extended our search by checking and cross-checking the
reference lists of all identified studies and by means of extensive
searches by hand. In addition, we did not restrict our search to
English publications and included publications in all
languages.75 Nevertheless, it is likely that we
missed some publications; however, we do not think that omission of a
few, probably small, studies has influenced our results to an important
extent. Other sources of bias might be more important. Studies that
found rates for mortality and morbidity to be much higher than in the
literature may have been left unpublished, because public awareness of
these results might be disadvantageous for the neurosurgeon or the
hospital. This type of bias leads to an underestimation of mortality
and morbidity. Another type of bias is that a study on outcome after
operation for unruptured aneurysms is more likely to be
undertaken by a neurosurgeon with some interest in aneurysm
surgery than by a neurosurgeon without special interest. A neurosurgeon
with interest in aneurysm surgery probably performs more
operations, with inherently better results. Again, this type of bias
leads to too-favorable results. To prevent bias from highly selected
case reports, we excluded studies with data on <5 patients.
We included studies with direct clipping as method of treatment.
Methods other than clipping (such as wrapping and coating) do not
definitively exclude the aneurysm from the circulation and are
rarely applied today. Again, this restriction may have led to an
underestimation of postoperative mortality and morbidity because large
aneurysms, with inherent greater risks of complications, used
to be treated by coating or wrapping.
We could not perform univariate regression analysis
for the use of an operation microscope and experience of the surgeon
because of the limited number of studies providing data on these items.
Limited power may also explain why we did not observe a statistically
significant influence of some factors that are likely to influence
outcome, such as age and preoperative condition.
Multivariate regression analysis was possible
for a limited number of variables only (Table 2
We found 1 previous meta-analysis by King et
al76 on surgery for asymptomatic
unruptured aneurysms. This included 28 studies (733 patients)
published from 1966 onward and reported a mortality rate of 1.0% (95%
CI, 0.4% to 2.0%) and a morbidity rate of 4.1% (95% CI, 2.8% to
5.8%). These complication rates are lower than those in our
meta-analysis. The difference may be the result of several
factors: (1) the exclusion of symptomatic
aneurysms, (2) a higher proportion of small (<10 mm)
aneurysms and aneurysms located at the anterior
circulation (72% and 94%, respectively, against 54% and 70% in our
study), and (3) the less-complete study retrieval (the total number of
patients is less than one third of the number in our
meta-analysis).
We conclude that surgery for unruptured intracranial aneurysms
has an overall mortality of 2.6% and a morbidity of 10.9%. Half the
patients with postoperative morbidity became dependent in daily life.
The most important risk factors for poor outcome were giant
aneurysm size and location at the posterior circulation of the
aneurysm. For patients with nongiant anterior circulation
aneurysms, mortality is estimated at 0.8% and morbidity is
1.9%; for patients with giant posterior circulation aneurysms,
estimations are 9.6% for mortality and 37.9% for morbidity. These
results should be taken into account when making a balanced decision on
whether to proceed with surgery in an individual patient with an
unruptured aneurysm.
Received March 24, 1998;
revision received May 15, 1998;
accepted May 15, 1998.
© 1998 American Heart Association, Inc.
Original Contributions
Mortality and Morbidity of Surgery for Unruptured Intracranial Aneurysms
A Meta-Analysis
Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
Appendix 1
References
Background and Purpose—Greater
availability and improvement of neuroradiological techniques have
resulted in more frequent detection of unruptured aneurysms.
Because prognosis of subarachnoid hemorrhage is still
poor, preventive surgery is increasingly considered as a therapeutic
option. Elective surgery requires reliable data on its risks.
Therefore, we performed a meta-analysis on the mortality and
morbidity of surgery for unruptured intracranial aneurysms.
Key Words: aneurysm, unruptured • cerebral aneurysm • meta-analysis • surgery
Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
Appendix 1
References
Prognosis of
subarachnoid hemorrhage (SAH) has improved slightly
over the last 3 decades, but outcome is still poor, with a
case-fatality rate of 
50% and a dependency rate of 10% to
20%.1 The overall annual risk of rupture of
intact intracranial aneurysms is 1.9%.2
Supported by some decision analyses,3 4 5 6 7
many neurologists and neurosurgeons advise preventive surgery for
unruptured aneurysms, at least under some circumstances. This
advice applies not only to additional aneurysms found in
patients with SAH from a ruptured aneurysm or to
symptomatic unruptured aneurysms but also to
incidental aneurysms. Improvement and greater availability of
neuroradiological techniques such as CT or MR angiography have led to
increases in fortuitous and intentional detection of these incidental
aneurysms. Intentional detection can result from screening
programs in patients with polycystic kidney disease or with a family
history of intracranial aneurysms.8 9
Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
Appendix 1
References
Eligible Studies
All studies on mortality and morbidity of surgery for unruptured
aneurysms published in journals, books, or book chapters from
1966 through June 1996 were eligible for our meta-analysis. We
accepted studies in all languages. Each study had to provide data on
postoperative mortality or morbidity of at least 5 adult patients. We
included all types of unruptured aneurysms: incidental,
symptomatic, or additional to a ruptured aneurysm
(also referred to as multiple). In cases of multiple aneurysm,
the unruptured aneurysm must have been surgically treated in a
separate procedure. The method of operation had to be clipping.
Patients who received other treatments for their unruptured
aneurysms (such as wrapping, trapping, coating, or
embolization) were excluded. Studies describing surgical results not
for each patient individually but for the complete patient group were
included only if at least 90% of patients were treated by direct clip
placement. We excluded mycotic, bacterial, posttraumatic, and
dissecting aneurysms and aneurysms in the cavernous
sinus. A list of excluded studies and the corresponding reasons for
exclusion is available on request.
To identify studies published between 1966 and June 1996, we
performed an extensive Medline search from 1966 onward (with the use of
13 key words in all relevant combinations) and a search by hand of 18
relevant general medical, neurological, and neurosurgical journals from
1990 onward; we also scrutinized the reference lists of all retrieved
publications for additional studies. The references of the publications
thus found were checked again for additional studies. This method of
cross-checking was continued until no further publications were found.
In the case of overlapping study populations, we excluded patients
described twice or used the most recent publication.
Two readers (T.R. and G.R. or M.L.) independently
assessed eligibility of studies and extracted data from the included
studies on the following items: year of publication; midyear of study
(defined as average calendar year of surgery); language; study design
(prospective or retrospective); use of operation microscope; experience
of the surgeon; number of patients; sex and age of patients; presence
of polycystic kidney disease or familial aneurysms;
preoperative condition of the patient (by Rankin score whenever
possible)10 ; number, site, and size of
aneurysms; presenting symptom (SAH from another
aneurysm, symptomatic or incidental as defined by
the original authors); criteria for postoperative mortality and
morbidity; results of postoperative angiography; duration of
follow-up; judgment of outcome (by neurosurgeon or independent
physician); number of patients with transient morbidity; and finally
number of patients with postoperative mortality and morbidity.
Mortality was defined as all-cause postoperative mortality. Morbidity
was defined as all permanent morbidity (eg, any neurological or other
deficit) not present before operation and was specified by Rankin
score when possible. If outcome was described in different categories
(eg, good, fair, poor), any outcome except the most favorable was
considered as morbidity.
We calculated the percentage of mortality and morbidity for each
study separately and all studies combined. Corresponding exact 95%
confidence intervals (CIs) for single proportions were determined. We
used univariate and multivariate weighted
linear regression to evaluate the influence on postoperative mortality
and morbidity of the following variables: study design; language of
publication; year of publication; midyear of study; sex and age of
subjects; preoperative Rankin score; site, size, and
presentation of aneurysms (additional,
symptomatic, or incidental); and duration of follow-up. The
number of patients per study was used as a weighting factor, so that
larger studies had more impact than small studies. Because the number
of studies with data on the use of operation microscope or on
experience of the neurosurgeon was limited, we could not perform
univariate linear regression analyses for these 2
items. Finally, we calculated postoperative mortality and morbidity in
the subgroup of studies that fulfilled the following 3 criteria for
"studies of good quality": clear definitions of outcome measures,
no selection of specific groups of patients or aneurysms, and
predefined moment of follow-up.
Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
Appendix 1
References
A total of 394 studies in 15 different languages were read and
considered for this meta-analysis. Sixty-one studies with 2460
patients (varying from 6 to 331 patients per study) met all inclusion
criteria
(Figure
).11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71
The number of aneurysms was at least 2568. We tried to exclude
patients who were included in more than 1 study, but for approximately
30 patients we could not rule out double counting because of an
insufficient description in the parent publications.
View larger version (38K):
[in a new window]
Figure 1. Overview of included studies and their
characteristics.
The median year of publication was 1987 (range, 1970 to 1996).
Midyear of surgery ranged from 1959 to 1992 (median, 1981). Languages
of publication were English (n=50), French (n=5), Japanese (n=5), and
Polish (n=1). Only 8 studies were prospective; the other 53 were
retrospective or unspecified. Forty studies described patients selected
for aneurysm site (n=9), aneurysm size (n=7),
aneurysm presentation (multiple,
symptomatic, or incidental) (n=13), or other
characteristics (n=6); in 21 studies, there was no selection regarding
characteristics of aneurysms. In 18 studies, an operation
microscope was used; in 1 this was not the case (42 studies not
specified). Information on the neurosurgeons' experience was never
explicit. In almost all studies (55 of 61), the neurosurgeon performing
the operations was also the author of the study and observer of
postoperative outcome. In half of the studies (30 of 61), outcome was
classified by means of clearly defined outcome measures. Twenty-nine
studies specified the moment of follow-up: in 8 studies outcome was
evaluated at discharge, in 21 studies duration of follow-up was
reported (median, 24 weeks; range, 2 to 234 weeks).
Data on sex were provided for 705 of 2460 patients: 405 women
(57.4%) and 300 men (42.6%). Data on age were available for 757
patients: mean age was 50.2 years (range, 15 to 79 years). The
preoperative condition of the patients was described in 33 studies (882
patients). Eighty-one patients (9.2%) had no symptoms or signs, 795
patients (90.1%) were independent in daily life but had symptoms or
signs (from a symptomatic unruptured aneurysm, a
previous SAH, or unrelated diseases), and 6 patients (0.7%) were
dependent in daily life. None of the studies contained information on
the presence of polycystic kidney disease. Ten patients were known to
have familial aneurysms.
In 2460 procedures, at least 2568 aneurysms were clipped;
thus, 108 patients received treatment for more than 1 unruptured
aneurysm in 1 procedure. Data on aneurysm site were
available in 40 studies for 1324 aneurysms. The majority (934
aneurysms; 70.3%) were located in the anterior circulation
(carotid artery or its branches, anterior and middle cerebral arteries,
anterior communicating artery); fewer (395 aneurysms; 29.7%)
were in the posterior circulation (basilar, vertebral, and posterior
cerebral arteries). Twenty-nine studies provided data on
aneurysm size: 691 (54.4%) were <10 mm, 235 (18.5%)
were between 10 and 25 mm, and 345 (27.1%) were giant
aneurysms (
25 mm). For 1252 patients, information was
available on the presentation of the unruptured
aneurysms: 430 patients (34.3%) had SAH and 1 or more
additional unruptured aneurysms, 358 patients (28.6%) had
asymptomatic aneurysms discovered by screening or
during workup for another neurological disease, and in 464 patients
(37.1%) aneurysms were symptomatic (as defined by
the original authors). One third of patients categorized as
symptomatic in the original studies had only nonspecific
symptoms such as headache or dizziness; two thirds had objective signs
such as visual loss, cranial nerve palsy, or other neurological
deficits.
In 10 studies, a postoperative angiogram was performed to verify
adequate clip placement. The results of these angiograms were given in
only 5 studies with 158 patients: 11 aneurysms were clipped
incompletely.
In total, 64 of the 2460 patients died after the operation (2.6%;
95% CI, 2.% to 3.3%). Between studies, this proportion ranged from
0% (38 of 61 studies) to 29%. , middle
column), mortality appeared to be significantly related to the year of
publication, midyear of study, and site and size of aneurysms.
Mortality decreased (negative regression coefficients) with a more
recent year of publication, a more recent midyear of surgery, and a
higher proportion of anterior circulation aneurysms. Mortality
increased (positive regression coefficient) with a higher proportion of
giant aneurysms. All other items mentioned in Table 1,
including mean age and sex, were not significantly related to
postoperative mortality.
View this table:
[in a new window]
Table 1. Univariate Weighted Linear Regression
Analyses of Several Characteristics on Mortality and
Morbidity , right column),
year of publication and site (model 1) independently contributed to the
prediction of mortality in the 35 studies in which both characteristics
were available. Year of publication (model 2) failed to reach
statistical significance when combined with the item size, suggesting
that these 2 items are not completely independent. The coefficient of
size in these studies (model 2) was equal (0.08) for both
univariate and multivariate
analysis, which suggests that the increased risk associated
with giant aneurysms did not change in more recent years. In
model 3, site and size did not independently contribute to
postoperative mortality, which suggests a relation between the 2
variables (giant aneurysms being more often located at the
posterior circulation). Multivariate analyses
with midyear of study yielded essentially the same results as those
with year of publication.
View this table:
[in a new window]
Table 2. Multivariate Analyses for
Studies With Data on More Than 1 Prognostic Characteristic
Simultaneously
Fifty-one (of 61) studies with 2270 patients provided data on
postoperative morbidity. Permanent morbidity was found in 248 patients
(10.9%; 95% CI, 9.6% to 12.2%). In 47 studies, the severity of
postoperative morbidity was specified for 238 patients: 112 had
symptoms or signs but were independent in daily life and 126 were
dependent. These numbers indicate that about half of patients with
postoperative morbidity were dependent. 
, right column), morbidity was statistically related to site
and size of aneurysms. Morbidity decreased (negative regression
coefficient) with a higher proportion of anterior circulation
aneurysms and increased (positive regression coefficient) with
a higher proportion of giant aneurysms. All other items
mentioned in Table 1, including mean age and sex, were not of
significant prognostic value for postoperative morbidity. , model 4), the variables site and size
had independent prognostic value with regard to morbidity. However, the
coefficients of both variables decreased (from -0.21 to -0.11 and
from 0.36 to 0.25). This indicates, similar to the data on mortality,
that site and size of aneurysms are not completely independent
characteristics.
Seven studies fulfilled all 3 criteria of good quality (clearly
defined outcome measures, no selection of patients or
aneurysms, and a predefined moment of
follow-up).11 19 27 29 57 61 70 In these studies,
17 of 686 patients died after operation (2.5%; 95% CI, 1.5% to
3.9%). Data on morbidity were available in 5 of 7 studies: 80 of 629
patients had postoperative sequelae (12.7%; 95% CI, 10.1% to
15.3%). In these 7 studies, outcome was assessed after a mean
follow-up period of 2 weeks (1 study), 24 weeks (2 studies), or at
discharge (4 studies).
Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
Appendix 1
References
In this meta-analysis of 61 studies, we found that
clipping of unruptured aneurysms was associated with a
mortality of 2.6% (95% CI, 2.0% to 3.3%) and a morbidity of 10.9%
(95% CI, 9.6% to 12.2%). Half the patients with surgical morbidity
became dependent in daily life. A location on the posterior circulation
and giant size were the most important prognostic factors for poor
outcome. ). Patients with nongiant
aneurysms of the anterior circulation have an estimated
mortality of 0.8% and morbidity of 1.9%. Extremely high risks apply
for patients with giant posterior circulation aneurysms: 9.6%
mortality and 37.9% morbidity. Patients with giant anterior
circulation aneurysms have a 7.4% chance of death and 26.9%
of morbidity. For patients with nongiant posterior aneurysms,
this would be 3.0% and 12.9%, respectively. 25 mm. It would
have been preferable to make a further distinction between
aneurysms of 10 to 15 mm and of 15 to 25 mm. The
information on aneurysm size in the source publications was not
sufficient to allow for more detailed analysis. ) because few
studies provided data on more than 1 prognostic characteristic
simultaneously.
Appendix 1
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
Appendix 1
References
General formula: dependent=
+(ß1)x(variable
1)+(ß2)x(variable 2). % Mortality=3.0-0.02x(% anterior
aneurysms)+0.07x(% giant aneurysms). %
Morbidity=12.9-0.11x(% anterior aneurysms)+0.25x(% giant
aneurysms). In patients with anterior aneurysms: %
anterior aneurysms=100. In patients with posterior
aneurysms: % anterior aneurysms=0. In patients
with giant aneurysms: % giant aneurysms=100. In
patients with nongiant aneurysms: % giant
aneurysms=0.
Acknowledgments
We thank K. Nagashima, T. Mendel, V.L. Feigin, D. Buljevac, N.
Gortzak-Moorstein, C. Motto, J.W. Hop, L.M.P. Ramos, and L. Ming for
their indispensable help in translating articles and Prof J. van Gijn
for his comments on the manuscript.
References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
Appendix 1
References
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