Vascular Neurosurgery
16 
General Principles for the Management
of Ruptured and Unruptured
Intracranial Aneurysms
PANAGIOTIS MASTORAKOS, DALE DING, ERIC C. PETERSON, ROBERT M. STARKE
CLINICAL PEARLS
• The incidence of intracranial aneurysms is variable throughout
the world and is approximately 6% in the international
population, with higher rates in Asian/Finnish populations and
those with a high-risk profile. In patients without any risk
factors, the incidence is approximately 2%. Once the aneurysm
has ruptured, one-third will die, whereas 50% of survivors will
lead independent lives.
• The majority of intracranial aneurysms arise at branching
points of large arteries. Hemodynamic stress likely contributes
to both the initial development and subsequent growth.
Aneurysm formation can have many other associated
conditions, including autosomal dominant polycystic kidney
disease, Ehlers-Danlos syndrome, Loeys-Dietz syndrome,
Marfan syndrome, tuberous sclerosis, fibromuscular dysplasia,
and other genetic and structural predispositions.
• Approximately 25% to 50% of all patients have warning
symptoms that herald the onset of a major subarachnoid
hemorrhage (SAH). The patient’s description of the headache is
very important, as most involve a “thunderclap” onset or the
“worst headache of my life.” Computed tomography (CT) scans
detect SAH with high sensitivity. If the scan is negative but
suspicion remains high, a lumbar puncture may be performed.
Although CT angiography is good for imaging aneurysms
Introduction
Intracranial aneurysms (IAs) are vascular lesions, and this poses
a challenge for decision making and management. Morpho-
logically and pathologically, they encompass a variety of enti-
ties including saccular, fusiform, and dissecting aneurysms
with a wide variety of etiologic origins, including hemody-
namic, traumatic, and infectious. Although intervention in
most cases of ruptured intracranial aneurysms is indicated,
controversy exists regarding the management of unruptured
intracranial aneurysms (UIAs). Namely, the question for every
254
Downloaded for John Egbuji (johnegbuji@gmail.com) at University of Otago from ClinicalKey.com.au by Elsevier on November 08, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
greater than 2 mm, cerebral angiography remains the gold
standard for intracranial vascular imaging.
• The risk of rebleeding after the SAH is greatest on the first day
(4.1%). By day 14, the cumulative rebleed incidence is 19%.
Once an aneurysm is secure, the most significant cause of
morbidity and death is cerebral vasospasm. The onset of
cerebral vasospasm begins on day 3 and peaks between 7 and
14 days after the SAH. Seventy percent of patients develop
radiographic signs of vasospasm, and approximately 30%
develop clinical vasospasm requiring adjunctive therapy.
• The treatment goal of intracranial aneurysms is to exclude
them from the parent circulation. In ruptured aneurysms, this
must be done early and safely so that maximum treatment of
cerebral vasospasm can be administered if necessary.
Symptomatic vasospasm can be treated with triple H therapy
(involving hypertension, hypervolemia, and hemodilution) and
endovascular means, namely intraarterial injection of
vasodilators or angioplasty.
• To achieve the goal of multidisciplinary cerebrovascular care,
aneurysm patients are ideally treated at centers of excellence
that employ expertise in all areas of neurovascular care,
including endovascular, microvascular, and neurocritical care,
as well as neuroanesthesia.
UIA is whether the benefit of aneurysm occlusion via clipping
or coiling outweighs the risk of a possible subarachnoid hemor-
rhage. Our understanding of the pathobiology and patho-
physiology of this entity has significantly improved, leading to
improvements in epidemiology, biology, genetics, therapeutic
intervention, and clinical outcomes. However, our understand-
ing of the natural history of this disease remains limited,
rendering decision making regarding intervention complex.
Moreover, as technology advances and new techniques become
available for aneurysm obliteration, further questions arise
regarding the optimal treatment choice. This chapter provides
 CHAPTER 16  General Principles for the Management of Ruptured and Unruptured Intracranial Aneurysms 255

an overview of intracranial aneurysms, clinical presentations, rebleeding of 20% at 2 weeks, 33% at 1 month, and 50% at
current therapeutic options, and technical aspects of surgical 6 months, and then 3% per year thereafter. Additionally, up
treatment. Although intracranial aneurysms encompass a to 60% of survivors remain functionally dependent.15,16
diverse disease entity, this chapter focuses on the most common
type—that is, saccular aneurysms. Pathogenesis
Epidemiology Intracranial arteries are unique to the systemic vascular system
in that they lack the external elastic lamina present in extra-
Aneurysm prevalence is difficult to assess, due to clustering cranial vessels. The pathogenesis of intracranial aneurysms has
in various high-risk groups and the presence of asymptomatic been thought to be due to a number of congenital factors, such
lesions. Unruptured aneurysms are common and are diagnosed as vascular wall defects (ie, tunica media and elastic lamina),
in 2% to 3% of the population. They have been identified in hemodynamic load on tortuous segments and bends, and dis-
as many as 1% to 9% of general population autopsies. How- continuity of the tunica media at origins of small vessels from
ever, extreme variability has been observed among different larger parent vessels. Moreover, systemic factors are thought
autopsy studies and reviews. Ethnicity-dependent clustering of to contribute to aneurysm pathogenesis, such as degenera-
aneurysms is observed, with a higher prevalence in the Asian tive changes, hypertension, atherosclerosis, connective tissue
and Finnish populations (4%–9%), and as a result, a 6% disease, and hemodynamic stress.
prevalence has been reported in the international population. The majority of lesions are located at branching points along
This disease process affects females three times more frequently the proximal arterial tree, suggesting that hemodynamic factors
than males.1–3 play a significant role in aneurysm formation (Fig. 16.1). In
Although the most prevalent risk factors are modifiable, the addition, formation of de novo aneurysms has been shown to
strongest risk factors are thought to occur through genetic and occur at communicating arteries, and fatal rupture of aneu-
familial predisposition. In fact, genetic predisposition through rysms has occurred after recruitment of collateral blood flow
various systemic and syndromic conditions is thought to rep- through communicating arteries after internal carotid artery
resent approximately 10% to 12% of all aneurysms. Aneu- (ICA) occlusion. Furthermore, the incidence of aneurysms
rysms occur sporadically, but they may also occur as part as associated with high-flow states (eg, arteriovenous malforma-
of familial syndromes such as adult polycystic kidney disease tions) is higher than in the general population, and some of
(ADPKD),4 Marfan syndrome, Ehlers-Danlos (EDS) type IV, these lesions spontaneously regress after treatment of the vas-
Loeys-Dietz syndrome,5 fibromuscular dysplasia (FMD), Moya­ cular malformation. Finally, recurrent aneurysms can develop
moya, and sickle cell disease.6 Patients with one affected family after incomplete treatment, whether by endovascular or micro-
member have a 4% risk, whereas patients with two affected surgical means.17
family members have an 8% to 10% risk of harboring an aneu- Other factors related to aneurysm formation are trauma,
rysm.7 A large meta-analysis of 19 studies identified 19 single infection, and tumor emboli. Traumatic aneurysms are more
nucleotide polymorphisms (SNPs) associated with sporadic
UIAs, with strongest associations including the chromosome
9 CDKN2B antisense inhibitor gene, chromosome 8 near
the SOX17 transcription regulator gene, and chromosome 4
near the EDNRA gene.8 Ruigrok and colleagues reviewed the
genetics of intracranial aneurysms and reported that probable
loci included chromosomes 5q and 17cen, from which the
strongest associations code for versican, an extracellular matrix
protein, and TNFRSF13B, a transmembrane activator and a
calcium modulator ligand interactor, respectively.9 Other sug-
gestive loci are 1p34.3–p36.13, 7q11, 19q13.3, and Xp22.10,11
Smoking and hypertension are modifiable risk factors for
the development of aneurysms due to an induction of vascular
wall changes and a decrease in the size of the tunica media. Of
note, female smokers are at risk of both aneurysm growth and
de novo aneurysm formation. However, the prevalence of
lesions is still thought to be approximately 2% in those without
any known risk factors.12,13
The incidence of aneurysmal subarachnoid hemorrhage
varies from 6 to 26 per 100,000 per year. Women outnumber
men by 1.6 to 1, and the peak age is 40 to 60 years. Modifiable
risk factors for aneurysm rupture include alcohol use, smoking,
and hypertension.1,14 Untreated ruptured aneurysms carry a • Figure 16.1  Cerebral angiogram demonstrates a basilar apex cerebral
mortality of 20% to 30% in the first 2 weeks, with a risk of aneurysm.

Downloaded for John Egbuji (johnegbuji@gmail.com) at University of Otago from ClinicalKey.com.au by Elsevier on November 08, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
256 PART 3 Vascular Neurosurgery
often fusiform and located near the skull base. Infectious
aneurysms have a multitude of etiologic factors but most
commonly occur secondary to bacterial endocarditis. Finally,
aneurysms can result from tumor seeding of the arterial wall
through hematogenous spread and are most often related to
cardiac myxomas.
Hemodynamics has been shown to play an important role
in aneurysm rupture. Using computational fluid dynamics, it
has been demonstrated that high wall shear stress is responsible
for growth and rupture in high-flow aneurysms, whereas the
predominant factors causing rupture in low-flow aneurysms
are high intraaneurysmal pressure and flow stasis. Indeed, rup-
tured aneurysms have unstable flow patterns and a higher
average wall shear stress in the aneurysm sac than unruptured
ones.18,19
Natural History
The natural history of intracranial aneurysms can be separated
into two general areas: ruptured and unruptured. For patients
with unruptured intracranial aneurysms, the natural history is
difficult to resolve. Estimated rupture rates are approximately
1% to 2% per year, with some populations (eg, Japanese
cohorts) reporting 3.2% per year.20,21 The current endovascular
or surgical treatment options to prevent aneurysmal rupture
are invasive and carry considerable risks of complications. For
some small aneurysms in the anterior circulation, the predicted
risk of rupture is much smaller than the risk of treatment
complications, and therefore many of these small aneurysms
are left untreated. However, a small proportion of these aneu-
rysms do rupture, and because these aneurysms by far outnum-
ber other aneurysms, most instances of aneurysmal subarachnoid
hemorrhage (SAH) are secondary to these small aneurysms.
Ultimately, a better risk prediction model and larger studies
are necessary to guide management of UIAs.
The International Study of Unruptured Intracranial Aneu-
rysms (ISUIA) is the best known and most frequently refer-
enced observational study on the natural history of unruptured
aneurysms >2 mm. Up until the ISUIA, preventive treatment
of UIAs had been performed for decades despite lack of evi-
dence of clinical benefit. This phenomenon probably stems
from a combination of factors, including the dismal outcome
after SAH and the more favorable outcome if patients were
treated electively. The retrospective part of ISUIA was pub-
lished in 1998 and featured 1450 patients with unruptured
aneurysms,22 whereas the prospective part of ISUIA was pub-
lished in 2003 and involved 61 centers and 1692 patients.15
The retrospective analysis suggested that aneurysms <10 mm
had an annual rupture risk of 0.5% and that the rate of
surgery-related morbidity and mortality greatly exceeded the
rupture rate of these aneurysms.22 The prospective analysis
found that, for anterior circulation aneurysms, those <7 mm
without a history of subarachnoid hemorrhage, <7 mm with
a history of subarachnoid hemorrhage, 7 to 12 mm, 13 to
24 mm, and ≥25 mm had 5-year rupture risks of 0%, 1.5%,
2.6%, 14.5%, and 40%, respectively. For posterior communi-
cating artery (PCOM) and posterior circulation aneurysms,
Downloaded for John Egbuji (johnegbuji@gmail.com) at University of Otago from ClinicalKey.com.au by Elsevier on November 08, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
those <7 mm, 7 to 12 mm, 13 to 24 mm, and ≥25 mm had
5-year rupture risks of 2.5%, 14.5%, 18.4%, and 50%, respec-
tively.15 One of the largest issues with ISUIA is that observa-
tional studies have reported a higher natural history rupture
rate than that reported by ISUIA. The historical risk of aneu-
rysm rupture is 1% to 2.5% per year, whereas ISUIA deter-
mined an annual rupture rate of 0.07% for aneurysms <10 mm.
Possibilities for the low rupture rates include the exclusion of
patients likely to get treatment (young or symptomatic patients)
and the inclusion of cavernous aneurysms, which are much less
likely to bleed than aneurysms of other locations. This is of
particular concern, as many observational studies have reported
that most cases of spontaneous SAH occur in aneurysms less
than 7 to 10 mm in diameter.23
The Unruptured Cerebral Aneurysm Study of Japan (UCAS)
was a Japanese observational prospective study of UIAs 3 mm
or larger (N = 5720, 6697 aneurysms). UCAS recruited
patients ≥20 years old (mean age 62.5 years) with UIAs
between 2001 and 2004.21 The annual rupture rate was 0.95%.
Similar to ISUIA, UCAS showed that the natural history of a
UIA is influenced by size and location, but an association with
the presence of a daughter sac was also identified. In contrast
to ISUIA, UCAS demonstrated that anterior circulation aneu-
rysms <7 mm still had a considerable rupture risk. Also,
although ISUIA showed that posterior circulation and PCOM
aneurysms were more prone to rupture, UCAS found that
posterior circulation aneurysms were not more prone to
rupture.21 It is important to note the difference in population
between these two studies; specifically, in ISUIA, 90% of the
cohort was Caucasian, whereas UCAS was based on a Japanese
population. In summary, UCAS identified risk factors for
aneurysm rupture that included anterior communicating
artery (ACOM) and PCOM aneurysm locations, the presence
of a daughter sac, and size >7 mm.
Another study contributing to our knowledge of UIA
natural history is the Familial Intracranial Aneurysm (FIA)
study, which examined the rupture risk of familial aneurysms
compared to those of sporadic aneurysms.24 In this study, 548
first-degree unaffected relatives within a family with at least 2
affected relatives underwent magnetic resonance angiography
(MRA) screening. Among those patients, 113 had UIAs; only
5 were greater than 7 mm. The annual rupture risk was found
to be 1.2%, which is 17-fold higher than a matched cohort
from ISUIA. Therefore small UIAs in patients with familial
aneurysms may have higher rupture risks than sporadic UIAs
of similar size.25
The decision of whether to treat saccular UIAs is complicated
by limitations in current knowledge of their natural history.
Until now, data were focused on aneurysm characteristics. The
PHASES (population, hypertension, age, size of aneurysm,
earlier SAH from another aneurysm, site of aneurysm) score
combined individual patient data from six prospective cohort
studies to determine predictors of UIA rupture, and then con-
structed a risk prediction chart to estimate the 5-year rupture
risk.26 A practical risk score was thus constructed, taking into
account geographic location, hypertension, patient age, aneu-
rysm size, earlier SAH, and aneurysm site. Gender, smoking
 CHAPTER 16  General Principles for the Management of Ruptured and Unruptured Intracranial Aneurysms 257

status, and the presence of multiple aneurysms did not have Clinical Presentation
an important effect on rupture risk when these other risk
factors were accounted for. That does not mean that they are Intracranial aneurysms can present as asymptomatic incidental
not important, but rather that they have no added predictive findings, with cranial nerve and other neurologic deficits, as
value when taking into account the six factors that constitute a sentinel event, or with SAH. UIAs are usually found inci-
the PHASES score—that is, the data should not be inter- dentally, with no associated symptoms. When symptoms are
preted as meaning smoking has no effect on rupture risk.26 The present due to compression and mass effect from the aneu-
limitations of this study include the use of different imaging rysm, middle cerebral artery (MCA) aneurysms may cause
modalities across studies to assess aneurysm size, as well as hemiparesis, visual field defects, and seizures; PCOM or basilar
the potential for selection bias, because patients in ISUIA or artery aneurysms may cause oculomotor palsy and brainstem
UCAS may be treated if the aneurysm grows, thus remov- compression; and cavernous ICA aneurysms can result in
ing a potential ruptured aneurysm patient from the cohort. cavernous sinus syndromes. Thromboembolic complications
Nowadays, a pure natural history study is impossible; only the from progressive thrombosis of large or giant aneurysms may
older Finnish study was done in a time period in which UIAs result in transient ischemic attacks or stroke. Other common
were not treated, which might explain the increased rupture neurologic findings include visual loss (eg, afferent pupillary
rate in this Finnish cohort.27 The PHASES score has also been defect), trigeminal symptoms, abducens nerve palsy, nystag-
associated with aneurysm growth.28 A prospective study of mus, vertigo, persistent nausea, and altered mental status
three tertiary centers demonstrated 12% growth during mean (Fig. 16.2).34
follow-up of 2.7 patient years. The initial aneurysm size was Approximately 25% of patients who present with SAH
the strongest predictor for growth, with a trend toward pos- report sentinel headaches in the weeks prior to presentation.
terior circulation location. Higher PHASES scores are associ- These sentinel events are thought to be due to minor leaks or
ated with an increased risk of UIA growth, and importantly, acute aneurysm growth. Earlier diagnosis through aggressive
aneurysm growth has been shown to be a surrogate outcome workup of possible sentinel events can prevent SAH and
measure of aneurysm rupture.28 improve outcomes. Any sudden onset thunderclap headache
An important limitation of these studies is that they do should be assumed to be related to an intracranial aneurysm
not take aneurysm morphology into account; UCAS only until proved otherwise.
accounted for daughter blebs.21 Aneurysm morphology influ- For patients who present with overt aneurysm rupture, the
ences wall shear stress, which influences growth and rupture. most common clinical symptoms and signs are the sudden
Smaller studies have attempted to define image-based morpho- onset of the worst headache of their life, severe nausea and
logic parameters as predictors of aneurysm rupture.29,30 More vomiting, altered mental status, nuchal rigidity, and loss of
specifically, neck width, dome width, aneurysm shape, aspect consciousness. It is of paramount importance to identify these
ratio (height/neck width), and bottleneck factor (dome width/
neck width) have been examined.31 Among these, a higher
aspect ratio (>1.6) is thought to be associated with an increased
rupture risk.30 Other morphologic characteristics, such as lobu-
lations, daughter sacs, and surface irregularity, have long been
associated with higher rupture risk. Finally, the hemodynamics
of the surrounding vasculature may put a particular UIA at a
greater risk of rupture (eg, dominant A1 feeding into an ante-
rior communicating artery aneurysm).32 Given the broad spec-
trum of intracranial aneurysms, a balance of prospective data
and clinical experience is necessary to properly and individu-
ally assess an individual patient’s rupture risk.
In case of rupture, approximately one-third of patients will
not survive 2 weeks after SAH, another one-third will survive
but be functionally dependent, and the last one-third will
survive and be functionally independent. The peak risk of
rehemorrhage is within the first 24 to 48 hours, with a 4%
rerupture risk within the first 24 hours and a 30% rebleeding
risk within 2 weeks for untreated lesions. Although advances
in neurocritical care have increased the survivability of aneu-
rysmal SAH, neurologic morbidity rate remains about the
same. The greatest risk after the initial aneurysmal rupture is
for rerupture. Once the aneurysm is secure, the greatest risk is
of delayed cerebral ischemia and cerebral vasospasm, thereby • Figure 16.2  MRI fluid attenuation inversion recovery (FLAIR) sequence
emphasizing the importance of early intervention and close demonstrates a basilar artery aneurysm with significant associated mass
monitoring in the postrupture period.33 effect on the brainstem.

Downloaded for John Egbuji (johnegbuji@gmail.com) at University of Otago from ClinicalKey.com.au by Elsevier on November 08, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
258 PART 3 Vascular Neurosurgery
patients, because aneurysmal rerupture has devastating conse-
quences, with mortality rates greater than 50%.
In 1968 Hunt and Hess documented the clinical grade of
patients and their outcomes following surgery, noting that
patients with good grades (ie, I–III) performed better in
surgery, whereas those with grades IV and V performed poorly.
Further, waiting until a grade IV or V SAH patient improved
to a lower grade provided them with a better prognosis than
operating on them in a poor state.35 Approximately 35% to
50% of poor grade patients have improved neurologic outcome
with aggressive medical management. Of particular impor-
tance is the use of ventriculostomy, which may differentiate
patients with poor grade due to cerebrovascular effects of SAH
versus those with hydrocephalus as sequelae of SAH. Due to
the poor tolerance of high-grade patients to surgical manipula-
tion, medical management, ventriculostomy, and endovascular
treatment are the typical course, unless mass effect due to the
presence of a clot is contributing to the obtunded state of the
patient. Evidence of intracranial pressure incompatible with
life or absent filling of vascular territories may be contraindica-
tions to intervention. The World Federation of Neurosurgical
Societies (WFNS) scale is an alternative grading system, which
uses a combination of the Glasgow Coma Scale (GCS) and the
presence of focal neurologic deficit.36
Diagnosis
Computed tomography angiography (CTA) and MRA are now
being used extensively in the evaluation of intracranial vascular
lesions, but they are not sensitive enough to consistently detect
aneurysms <3 mm. CTA has average specificity of 96% to
98% (90%–94% for aneurysms smaller than 3 mm and up to
100% for aneurysms larger than 4 mm) and sensitivity rates
of 96% to 98% (Fig. 16.3).37 In fact, some investigators have
• Figure 16.3  Middle cerebral artery aneurysm on CT angiography.
Downloaded for John Egbuji (johnegbuji@gmail.com) at University of Otago from ClinicalKey.com.au by Elsevier on November 08, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
proposed that CTA could replace DSA as the most reliable
means to detect intracranial aneurysms.38 The advantage of
CTA includes its short duration and good bone imaging for
surgical planning. The limitations of CTA include lack of sen-
sitivity for lesions involving the carotid artery at the skull base
or the contrast-filled cavernous sinuses. The sensitivity of MRA
is 70% to 99%, a specificity of 100%. Three-dimensional
time-of-flight (TOF) MRA is the most widely used technique,
providing good spatial resolution; it is relatively insensitive to
signal loss caused by turbulent flow and can be performed
within a time span allowing for an anatomic magnetic reso-
nance imaging (MRI) during the same session. However, the
procedure duration is too long for critically ill patients, and
this modality is very sensitive to motion artifact.37 Catheter
digital subtraction angiography (DSA) is the gold standard of
evaluation for aneurysms; this constitutes an invasive proce-
dure with possible complications that include a 1% risk for
a transient ischemic attack, a 0.01% risk of stroke, a 0.05%
to 0.55% risk of femoral artery injury, a 7% to 11% risk of
groin hematoma, and a 1% to 2% risk of renal complications.39
Regarding the diagnosis of SAH, with the technologic
advancements of computed tomography (CT) scanners, the
sensitivity/specificity of SAH detection is greater than 98% in
the first 2 days,40 and with fifth-generation scanners it has been
reported to be 100%.41 As such, lumbar puncture is not neces-
sarily indicated unless the insinuating event happened at least
3 days prior to presentation or if the head CT is negative,
despite strong clinical suspicion. A lumbar puncture is used to
detect evidence of red blood cells and xanthochromia.
Subarachnoid Hemorrhage
The treatment of SAH includes neurointensive care and
medical management. The options for treatment of intra-
cranial aneurysms are observation, endovascular occlusion,
microsurgical clipping, or a combination of approaches (Fig.
16.4). In 1990 the International Study of Timing of Aneurysm
Surgery (ISTAS) was a prospective observational study that
evaluated the effect of timing of surgical intervention on aneu-
rysmal SAH outcomes. The overall comparison demonstrated
that considerable morbidity and mortality occurred after early
surgery (days 0–3) and prior to late surgery (post day 10). The
mortality associated with intervening events while waiting for
delayed surgery nearly equaled the postoperative mortality rate
following early surgery. Surgery planned for days 7 to 10 had
both high perioperative and postoperative complication rates,
resulting in an overall higher mortality level.42,43 The general
trend following ISTAS was that surgeons favored operating
earlier on ruptured aneurysms, given the lack of difference in
patient outcomes in early or late surgery and the opportunity
for aggressive medical management, including the ability to
treat vasospasm with hypertensive therapy after securing the
aneurysm. However, since this study, the techniques for the
treatment of subarachnoid hemorrhage have progressed, thus
questioning the validity of the conclusions in the modern era.44
The goal of treatment is to exclude the aneurysm from
circulation as soon as possible in order to minimize the risk
 CHAPTER 16  General Principles for the Management of Ruptured and Unruptured Intracranial Aneurysms 259

• Figure 16.4  CT scan demonstrates subarachnoid and intraventricular hemorrhage from a ruptured
aneurysm.

of rebleeding, which is frequently devastating for the patient.
The peak incidence of rehemorrhage for ruptured aneurysms
occurs within the first 48 hours. Importantly though, if a
patient presents at off hours, it is likely that the risks presented
by suboptimal operating room and staff conditions may out-
weigh the risks of postponing the procedure. It is therefore
recommended to perform aneurysm surgery on the next elec-
tive surgical day, when an appropriate neurosurgical team can
be assembled. Another factor to be taken into account is the
onset of vasospasm. A ruptured aneurysm should be secured
before the onset of delayed cerebral ischemia so as to avoid the
risk of rehemorrhage with the implementation of hypertensive
and hypervolemic therapy for vasospasm. Despite this ratio-
nale, the issue of treatment timing remains somewhat contro-
versial. Some contemporary cerebrovascular surgeons suggest
treating all good grade patients within 24 hours of admission
unless medically unsafe. For poor grade patients, the sugges-
tion is that a ventriculostomy is placed and that they undergo
endovascular or surgical treatment within 24 to 48 hours of
presentation.
Systemic circumstances may prevent a patient from being
ready for aneurysm treatment. Antifibrinolytic therapy (eg,
tranexamic acid) has been suggested to aid in reducing the
risk of rebleeding. The International Cooperative Aneurysm

Downloaded for John Egbuji (johnegbuji@gmail.com) at University of Otago from ClinicalKey.com.au by Elsevier on November 08, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
260 PART 3 Vascular Neurosurgery
Study found that the rebleeding rate at 14 days decreased to
11.7% with the use of antifibrinolytics, compared to 19.4%
without antifibrinolytics. However, the use of antifibrino­
lytics increases the risk of ischemic events in the setting of
vasospasm, thus equalizing the mortality rates between the
two groups.45
Cerebral vasospasm (CVS) is the leading cause of mor-
bidity and death following aneurysmal SAH.46 CVS results
in permanent neurologic morbidity in 7% of SAH patients
and may be fatal in 7%. This entity can be defined as clini-
cal vasospasm, which is delayed ischemic neurologic deficit
(DIND) following SAH characterized by altered mental status
(AMS) or delayed ischemic neurologic deficit. Radiographic
vasospasm is defined as arterial narrowing as diagnosed with
imaging modalities such as CTA or DSA. Angiographic and
clinical vasospasm may not coincide—that is, angiographic
CVS may occur without a clinical deficit and DIND may be
diagnosed without radiographic evidence of vasospasm. Angio-
graphic CVS is identified in 30% to 70% of aneurysmal SAH
patients; however, symptomatic CVS is diagnosed in only 20%
to 30% of aneurysmal SAH patients. CVS typically occurs 3
to 14 days post SAH and resolves slowly over 1 month. The
clinical exam on presentation (based on the Hunt and Hess or
WFNS grading scales) and the amount of intracranial blood
(as graded by the modified Fisher score) independently cor-
relate with the risk of DIND.35,47 The pathogenesis of CVS is
not well understood, although multiple studies have demon-
strated that endothelin-1, as well as a number of inflammatory
markers, contribute to the development of CVS.48
CVS is primarily diagnosed using clinical criteria; patients
require diligent monitoring and treatment for up to 14 days
after SAH. In addition to DSA demonstrating CVS, serial
transcranial Doppler (TCD), CTA, and MRA may detect evi-
dence of CVS. Moreover, cerebral blood flow alterations
may be investigated using MRI (diffusion-weighted imaging/
perfusion-weighted imaging) and CT perfusion.
The medical management of CVS has traditionally been
with triple-H therapy (ie, hemodilution, hypertension, and
hypervolemia), thus maximizing rheologic factors. However,
aggressive triple-H therapy has not been shown to be benefi-
cial, decreasing O2 transport capacity of blood and increas-
ing the risk of flash pulmonary edema. Therefore in the
setting of CVS, patients should be placed in a neurocritical
care setting, hypertension (systolic blood pressure 160–220)
should be encouraged, euvolemia (not hypervolemia) should
be promoted, and hemoconcentration that may occur in the
setting of dehydration due to salt wasting syndrome should
be avoided. Importantly, treatment and permissive hyperten-
sion may be driven by clinical exam and until the reversal
of neurologic deficit. In symptomatic CVS patients who are
refractory to triple-H therapy, endovascular intervention can
also be employed, which may involve intraarterial injection of
vasodilators or balloon angioplasty. In addition to spasm in the
large conducting vessels, the phenomenon of SAH also trig-
gers more complex events, which can lead to patchy infarcts in
areas apparently unaffected by angiographically evident vaso-
spasm. Euvolemia and nimodipine are used as prophylaxis
Downloaded for John Egbuji (johnegbuji@gmail.com) at University of Otago from ClinicalKey.com.au by Elsevier on November 08, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
against delayed ischemic neurologic deficits associated with
vasospasm.49
Treatment of Intracranial Aneurysms
The treatment approaches for aneurysms have undergone a
paradigm shift since the emergence of endovascular options
that have drastically increased the armamentarium for aneu-
rysm intervention. This renders the decision making regard-
ing treatment more complex, requiring an individualized
approach, which depends on aneurysm characteristics, rup-
ture status, patient characteristics, and physician and patient
preferences.
Treatment of Unruptured Aneurysms
The natural history of UIAs, as described earlier, contributes
to the decision-making process for aneurysm treatment. Cur-
rently, there is a lack of prospective randomized controlled
trials to guide therapy for UIAs. The majority of the published
literature for UIAs is retrospective in nature. Our best informa-
tion regarding the management of UIAs is based on observed
rates of complications in aneurysm treatment compared to the
natural history of unruptured aneurysms.
If conservative management is pursued, periodic follow-up
using MRA or CTA is warranted. There is no optimum inter-
val, but a minimum of annual studies for 3 years, and then
reduced frequency, has been suggested. Less frequent imaging
is required for very small (ie, 2–3 mm) aneurysms. It is impor-
tant to emphasize to patients the importance of modifiable risk
factors including smoking and Hypertension (HTN) and
alcohol (EtOH) use.50 The risk of aneurysm rupture after con-
firmation of aneurysm enlargement has been found to be
elevated. One study found that the rupture risk was 2.4% per
patient-year for aneurysms with evidence of enlargement, com-
pared to 0.2% per patient-year for aneurysms without growth.51
During the ISUIA study, 1900 UIA patients underwent sur-
gical treatment, whereas 451 underwent endovascular therapy.
Treatment was not randomized, and those who underwent
endovascular therapy were older, had larger aneurysms, and
more frequently had basilar tip aneurysms. Comparison of
outcomes demonstrated a treatment-related death of 1.8%
in the surgical group versus 2% in the endovascular group,
with a slightly higher rate of disability in the surgical group.
At 1-year follow-up, the overall morbidity and mortality for
patients undergoing surgical treatment was 12.6% versus 9.8%
in the endovascular group. Multivariate analysis demonstrated
that age >50 years, aneurysm size >12 mm, posterior circula-
tion aneurysm location, prior stroke, and localizing symptoms
(compressive neuropathies, etc.) were found to be predictors
of poor outcome in the surgical group. Aneurysm size was
similarly associated with worse outcome in the endovascular
group. Results from ISUIA indicate that age and aneurysm
morphology (ie, size and shape) are determinants of surgical
morbidity and mortality. Atherosclerotic or calcified walls pose
up to a 50% risk of ischemic complications following clipping,
and partially thrombosed aneurysms may similarly pose an
 CHAPTER 16  General Principles for the Management of Ruptured and Unruptured Intracranial Aneurysms
increased stroke risk. Posterior circulation aneurysms are also
associated with worse outcome.1,52
A retrospective cohort study of 2600 patients with UIAs
demonstrated that hospital death or discharge to a nursing
home or rehab center was much more common after surgical
compared to endovascular treatment (18.5% vs 10.6%, respec-
tively).53 Similarly, a report from the University of California,
San Francisco, in 2001 demonstrated that endovascular treat-
ment had an adverse outcome risk of 10% versus 25% for
surgical treatment.54 These reports suggest endovascular coiling
may be safer than clipping for UIAs. However, one must con-
sider that these studies are not randomized, even though most
patients who underwent endovascular therapy were older and
had more medical comorbidities than those who underwent
surgery.
Surgical management of aneurysms represents the tradi-
tional gold standard intervention because it reliably excludes
aneurysms from the circulation. At some centers, endovascular
treatments are overtaking microsurgical clipping for many
unruptured aneurysms. Occlusion rates are a central point
when considering in the risks and benefits of aneurysm treat-
ment and must be balanced against the morbidity and mortal-
ity associated with each treatment option.55 Most studies
evaluating endovascular occlusion rates report complete aneu-
rysmal obliteration in 50% to 70% of aneurysms and near
complete occlusion (>90% occlusion) in approximately 90%
of aneurysms immediately after embolization.56–60 Despite this
result, on follow-up imaging, as many as 32% of patients may
have some neck remnant. Furthermore, the progressive throm-
bosis rate of 25% and the overall recanalization rate of 49%,
which approaches 90% for giant aneurysms, suggest that
surgery may be necessary to achieve complete obliteration for
some cases.61,62 Although surgery physically excludes an aneu-
rysm, preventing aneurysm regrowth, endovascularly treated
aneurysms can theoretically grow and recur from any part of
the aneurysm wall because the aneurysm is not physically
excluded from the circulation. Importantly, surgical results for
MCA aneurysms have been excellent, raising the debate about
the respective roles of surgery and endovascular management
for aneurysms in this location. MCA aneurysms have long
been considered unfavorable for coiling based on their branch
anatomy, broad necks, and dysmorphic shapes. Therefore a
“clip first” policy has been suggested for these aneurysms.63
Stent assistance in aneurysm treatment emerged as an alter-
native to balloon remodeling in the late 1990s, and particularly
in the early 2000s with the development of the Neuroform
stent (Stryker, Kalamazoo, Michigan). The mechanical advan-
tages underlying endoluminal treatment for aneurysms are
threefold. First, the uncoupling of arterial pulsations between
the parent artery and aneurysm are thought to cause flow
disruption and improve the mean circulation time through the
aneurysm, thus increasing the likelihood of thrombosis. Fol-
lowing thrombosis, eventual degradation of the thrombus and
resorption by scavenger cells can lead to aneurysm shrinkage.
Second, once implanted into the parent artery, it is thought to
cause a growth effect that reinforces the parent artery at the
neck and reduces the likelihood of aneurysm recurrence. Third,
Downloaded for John Egbuji (johnegbuji@gmail.com) at University of Otago from ClinicalKey.com.au by Elsevier on November 08, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
261
it provides a mechanical scaffold to promote neointimal growth
across the neck, thereby promoting obliteration.64 Benitez and
colleagues published one of the earliest reports of stent-assisted
coiling in 2002, noting successful treatment in 41 of 49
patients. However, an overall complication rate of 10.7% was
noted, including death in 5 patients (8.9%) and thromboem-
bolic events in 4 (7%).65 In a prospective study of stent-assisted
coiling from the Cleveland Clinic, complete or near complete
immediate occlusion was achieved in 45.9% of patients, pro-
gressive thrombosis occurred in 52%, and recanalization was
evident in 23%. It is important to note that although these
numbers are not superior to coiling alone, the aneurysm mor-
phology within this cohort was composed of broad necks,
fusiform aneurysms, giant aneurysms, and aneurysms with coil
compaction that were not suitable for standard coiling tech-
niques.66 Drawbacks to endoluminal therapy include the rate
of technical failure (more common in older models), throm-
boembolic complications (seen radiographically in up to 25%
of patients), in-stent stenosis, and the requirement for an anti-
platelet regimen, either preoperatively in UIA patients or
immediately following stent deployment in cases of SAH.
During the studies for use of the Neuroform, Enterprise
(Codman, Raynham, Massachusetts) and Leo stents (Balt,
Montmorency, France), it was noted that some patients who
were treated with stenting without concurrent coiling place-
ment had some resolution of their aneurysm due to spontane-
ous thrombosis. In some of these cases, multiple overlapping
stents were placed, increasing the surface area coverage and
further disrupting flow into the aneurysm. Following these
observations, flow-diverting stents, such as the pipeline embo-
lization device (PED; Chestnut Medical Technologies, Menlo
Park, California), were developed. These devices provide 30%
to 35% metal surface area. Physiologic studies have demon-
strated that changes occur immediately following stent deploy-
ment, with improved laminar flow through the parent vessel,
reduced intraaneurysmal flow, and gradual thrombosis with
subsequent degradation of the thrombus and aneurysm remod-
eling. The long-term effectiveness of endovascular treatment of
large and giant wide-neck aneurysms using traditional endo-
vascular techniques has been disappointing, with high recana-
lization and retreatment rates. Flow diversion with the PED
has been used as a standalone therapy for complex aneurysms,
showing a significant improvement in effectiveness compared
to conventional endovascular techniques, while demonstrating
a similar safety profile to stent-assisted coiling.67 The safety and
efficacy of these devices have been demonstrated in two pro-
spective trials: PED for Intracranial Treatment of Aneurysms
(PITA) and PED for Uncoilable and Failed Aneurysms (PUFS).
PITA was the first multicenter, single-arm clinical trial for PED
at three centers in Europe, which examined 31 patients with
wide-necked (>4 mm) UIAs at 30- and 180-day follow-up
intervals. The trial demonstrated technically successful deploy-
ment in 30/31 patients, complete obliteration in 93%, and
two major periprocedural strokes.68 The PUFS trial in 2013
was a prospective study of 107 patients with large (diameter
>10 mm), wide-necked, anterior circulation UIAs arising from
the petrous ICA segment to the superior hypophyseal artery.
262 PART 3 Vascular Neurosurgery
After 3 years of follow-up, complete occlusion was achieved in
71 of 76 cases, 5 retreatments with coils or PED were required,
there was no recanalization of a previously occluded aneurysm,
and serious adverse effects were noted in 3% of patients
without permanent neurologic sequelae; therefore this study
concluded that the PED is safe and effective for complex large
giant proximal ICA aneurysms.69,70 Next-generation flow
diverters include the Surpass stent (Stryker, Kalamazoo, Michi-
gan) and the Flow Redirection Endoluminal Device (FRED;
MicroVention, Inc., Tustin, California). The use of flow divert-
ers is limited by access difficulty and depends on ICA tortuos-
ity, as well as the need for dual antiplatelet therapy (DAPT).
The biggest consideration with flow diverters is the poten-
tial coverage of perforator branches, particularly those supply-
ing critical brain structures (eg, basal ganglia, thalamus,
brainstem). Under normal circumstances, branch vessels act as
a siphon, drawing flow away from the parent artery, such that
as long as an arterial to capillary gradient exists, the artery can
maintain patency with up to 50% surface area coverage of its
ostium. Preloading with DAPT is required for flow diversion,
hence acute SAH is a relative contraindication for the use of
these stents.
Treatment of Ruptured Aneurysms
The International Subarachnoid Aneurysm Trial (ISAT) was a
randomized, multicenter trial used to compare the safety and
efficacy of coiling versus clipping for ruptured aneurysms.71 In
this trial, 1070 patients were randomized to the clipping arm,
and 1073 were randomized to the coiling arm. The primary
outcome at 2 months and 1 year was the proportion of patients
who had a modified Rankin Scale (mRS) of 3 to 6 (function-
ally dependent or dead). Most patients had anterior circulation
aneurysms (only 2.7% were posterior circulation); this included
50.5% anterior communicating artery (ACA), 32.5% ICA,
and 14.1% MCA aneurysms. At the 1-year follow-up, 23.7%
of endovascular patients and 30.6% of surgical patients reached
the primary end point. There was a relative risk reduction of
22.6% and an absolute risk reduction of 6.9% for the endo-
vascular arm. Further, the rebleeding rate at 1 year was very
low (0.15% in the endovascular arm vs 0.07% in the surgical
arm). ISAT demonstrated that, for patients with ruptured
aneurysms treatable by either modality, the outcome was more
favorable for endovascular intervention. Of note, a large
number of the patients treated at trial centers were not included
in the study, as providers chose not to randomize them. This
raised concerns of selection bias. Moreover, ISAT’s advantages
in outcome with coiling vanished at the 5-year follow-up, due
to aneurysm recurrences, rehemorrhages, and morbidity asso-
ciated with retreatments.
Following the results of ISAT, the Barrow Ruptured Aneu-
rysm Trial (BRAT) sought to further evaluate the safety and
efficacy of clipping versus coiling for acutely ruptured aneu-
rysms.72 In this study, 500 patients were enrolled, and 472 were
eligible for analysis. Of these, 239 patients were randomized
to clipping, and 233 were randomized to coiling. Once
assigned, neurosurgeons could review imaging and treatment
Downloaded for John Egbuji (johnegbuji@gmail.com) at University of Otago from ClinicalKey.com.au by Elsevier on November 08, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
options. If the assigned physician thought the patient was
better treated with the other modality, crossing over was per-
mitted. At the 1-year follow-up, 33.7% of surgical patients
versus 23.2% of endovascular patients had a poor outcome
(defined as mRS 3–6). The odds ratio for poor outcome after
clipping versus coiling was 1.68. The absolute difference was
10.5%, in favor of endovascular treatment. When patients
were evaluated based on an as-treated analysis, the absolute
difference was even greater (15.5%). Furthermore, no patient
suffered repeat subarachnoid hemorrhage in the coiling group.
Even after adjusting for confounders, surgical clipping had an
odds ratio of 1.72 for poor outcome at 1 year. Overall, the
results of BRAT were similar to those for ISAT. Of note, a
greater number of patients crossed over from coiling to clip-
ping than vice versa (75 vs 4 patients, respectively). Specifically,
14 patients had hematomas, which required surgical evacua-
tion; some aneurysms were thought to be too small to treat
endovascularly; the neck diameter was unfavorable; or branch
vessel anatomy prevented occlusion. This is important, as it
emphasizes the patient-specific aspects of BRAT, which con-
cluded that for aneurysms that are equally treatable by clipping
or coiling, coiling is the safer option; however, clipping is more
versatile, as over 30% of ruptured aneurysms in the trial were
unable to undergo endovascular treatment.72
At the 3-year follow-up, BRAT noted some important find-
ings; the risk of poor outcome in patients who underwent
clipping was no longer statistically significant (35.8% vs 30%;
p = .25). This was particularly true for anterior circulation
aneurysms. When stratified by location, however, posterior
circulation aneurysms continued to demonstrate better out-
comes with endovascular intervention. Importantly, random-
ization was not even for posterior circulation aneurysms, with
18 of 21 posterior inferior cerebellar artery (PICA) aneurysms
and 5 of 6 superior cerebellar artery (SCA) aneurysms allocated
to treatment by clipping. Interestingly, and congruent with
other observations questioning the durability of coiling, the
degree of aneurysm obliteration was higher and the rates of
aneurysm recurrence and retreatment were lower in the clip-
ping cohort. Although there were no occurrences of rebleeding
after year 1, 10.6% of coiling patients underwent retreatment
in the first year versus 4.5% of clipping patients, whereas two
more coiling patients underwent retreatment in the second and
third years. In total, 13% of coiling patients required retreat-
ment versus 5% of clipping patients (p = .01). Complete
obliteration was achieved in 58% of coiling patients after
initial treatment, which decreased to 52% at the 3-year follow-
up, whereas complete obliteration was achieved in 85% of
clipping patients, which was 87% at the 3-year follow-up.73 At
the 6-year follow-up of BRAT, there was again no difference
in outcomes for anterior circulation aneurysms. The occlusion
rates of the clipping versus coiling groups were 96% and 48%,
respectively; and the overall retreatment rates of the clipping
and coiling groups were 4.6% and 16.4%, respectively.74
Multiple factors need to be considered in the decision-
making process of clipping versus coiling for ruptured
aneurysms. The need for hematoma evacuation, young age,
wide-necked morphology, MCA aneurysm location, complex
 CHAPTER 16  General Principles for the Management of Ruptured and Unruptured Intracranial Aneurysms
or unfavorable branch vessel anatomy, and tortuous proximal
vasculature are factors that tend to favor clipping. In contrast,
a high Hunt and Hess grade (III–V), cerebral edema, the need
for anticoagulation, posterior circulation aneurysm location,
dome-to-neck ratio >2, fusiform morphology, and multiple
aneurysms amenable to simultaneous endovascular treatment
are factors that tend to favor coiling. Regardless of the approach,
the Cerebral Aneurysm Rerupture After Treatment (CARAT)
study demonstrated that the degree of aneurysm occlusion at
the initial treatment is a strong predictor of subsequent rerup-
ture in aneurysmal SAH patients, thus justifying attempts to
completely occlude aneurysms. In the CARAT study, the
overall risk of rerupture tended to be greater after coiling com-
pared with clipping, but the difference was not statistically
significant.75
Conclusion
Intracranial aneurysms are responsible for significant rates of
morbidity and mortality despite decades of advanced knowl-
edge and research. The natural history of unruptured intra-
cranial aneurysms is still controversial, especially with regard
to aneurysms smaller than 7 mm. Other morphologic factors
have been associated with increased rupture risk, but no one
factor seems able to predict rupture. Each individual unrup-
tured aneurysm should be evaluated with all aspects taken into
Downloaded for John Egbuji (johnegbuji@gmail.com) at University of Otago from ClinicalKey.com.au by Elsevier on November 08, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
263
consideration, including lesional characteristics and patient
comorbid conditions, as well as patients’ risk aversion and
expectations from the management plan. Contemporary man-
agement strategies should involve all aspects of neurovascular
care, including neuroendovascular physicians, neurocritical
care, and neuroanesthesia.
Selected Key References
Bederson JB, Connolly ES Jr, Batjer HH, et al. Guidelines for the man-
agement of aneurysmal subarachnoid hemorrhage: a statement for
healthcare professionals from a special writing group of the Stroke
Council, American Heart Association. Stroke. 2009;40(3):994-1025.
Lall RR, Eddleman CS, Bendok BR, et al. Unruptured intracranial aneu-
rysms and the assessment of rupture risk based on anatomical and
morphological factors: sifting through the sands of data. Neurosurg
Focus. 2009;26(5):E2.
Pluta RM, Hansen-Schwartz J, Dreier J, et al. Cerebral vasospasm fol-
lowing subarachnoid hemorrhage: time for a new world of thought.
Neurol Res. 2009;31(2):151-158.
Rabinstein AA. The AHA guidelines for the management of SAH:
what we know and so much we need to learn. Neurocrit Care.
2009;10(3):414-417.
Wiebers DO, Whisnant JP, Huston J 3rd, et al. Unruptured intracranial
aneurysms: natural history, clinical outcome, and risks of surgical and
endovascular treatment. Lancet. 2003;362(9378):103-110.
Please go to ExpertConsult.com to view the complete list of references.
 CHAPTER 16  General Principles for the Management of Ruptured and Unruptured Intracranial Aneurysms 263.e1
References
1. Weir B. Unruptured intracranial aneurysms: a review. J Neurosurg.
2002;96:3-42.
2. Hetts SW, Narvid J, Sanai N, et al. Intracranial aneurysms in child-
hood: 27-year single-institution experience. AJNR Am J Neuroradiol.
2009;30:1315-1324.
3. Nguyen TV, Chandrashekar K, Qin Z, et al. Epidemiology of intra-
cranial aneurysms of Mississippi: a 10-year (1997-2007) retrospec-
tive study. J Stroke Cerebrovasc Dis. 2009;18:374-380.
4. Chow CL, Ong AC. Autosomal dominant polycystic kidney disease.
Clin Med (Northfield Il). 2009;9:278-283.
5. Rodrigues VJ, Elsayed S, Loeys BL, et al. Neuroradiologic manifes-
tations of Loeys-Dietz syndrome type 1. AJNR Am J Neuroradiol.
2009;30:1614-1619.
6. Schievink WI. Genetics of intracranial aneurysms. Neurosurgery.
1997;40:651-662, discussion 662-653.
7. Foroud T, Sauerbeck L, Brown R, et al. Genome screen in familial
intracranial aneurysm. BMC Med Genet. 2009;10:3.
8. Alg VS, Sofat R, Houlden H, et al. Genetic risk factors for intra-
cranial aneurysms: a meta-analysis in more than 116,000 individu-
als. Neurology. 2013;80:2154-2165.
9. Ruigrok YM, Rinkel GJ. Genetics of intracranial aneurysms. Stroke.
2008;39:1049-1055.
10. Ruigrok YM, Rinkel GJ, Wijmenga C, et al. Association analysis
of genes involved in the maintenance of the integrity of the extra-
cellular matrix with intracranial aneurysms in a Japanese cohort.
Cerebrovasc Dis. 2009;28:131-134.
11. Shi C, Awad IA, Jafari N, et al. Genomics of human intracranial
aneurysm wall. Stroke. 2009;40:1252-1261.
12. Broderick JP, Viscoli CM, Brott T, et al. Major risk factors for
aneurysmal subarachnoid hemorrhage in the young are modifiable.
Stroke. 2003;34:1375-1381.
13. Clarke M. Systematic review of reviews of risk factors for intracranial
aneurysms. Neuroradiology. 2008;50:653-664.
14. de Rooij NK, Linn FH, van der Plas JA, et al. Incidence of sub-
arachnoid haemorrhage: a systematic review with emphasis on
region, age, gender and time trends. J Neurol Neurosurg Psychiatry.
2007;78:1365-1372.
15. Wiebers DO, Whisnant JP, Huston J 3rd, et al. Unruptured intra-
cranial aneurysms: natural history, clinical outcome, and risks of
surgical and endovascular treatment. Lancet. 2003;362:103-110.
16. Woo D, Khoury J, Haverbusch MM, et al. Smoking and family
history and risk of aneurysmal subarachnoid hemorrhage. Neurology.
2009;72:69-72.
17. Frosen J, Tulamo R, Paetau A, et al. Saccular intracranial aneu-
rysm: pathology and mechanisms. Acta Neuropathol. 2012;123:
773-786.
18. Shojima M, Oshima M, Takagi K, et al. Magnitude and role of
wall shear stress on cerebral aneurysm: computational fluid dynamic
study of 20 middle cerebral artery aneurysms. Stroke. 2004;35:
2500-2505.
19. Castro MA, Putman CM, Cebral JR. Computational fluid dynamics
modeling of intracranial aneurysms: effects of parent artery segmen-
tation on intra-aneurysmal hemodynamics. AJNR Am J Neuroradiol.
2006;27:1703-1709.
20. Ishibashi T, Murayama Y, Urashima M, et al. Unruptured intra-
cranial aneurysms: incidence of rupture and risk factors. Stroke.
2009;40:313-316.
21. Investigators UJ, Morita A, Kirino T, et al. The natural course of
unruptured cerebral aneurysms in a Japanese cohort. N Engl J Med.
2012;366:2474-2482.
Downloaded for John Egbuji (johnegbuji@gmail.com) at University of Otago from ClinicalKey.com.au by Elsevier on November 08, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
22. International Study of Unruptured Intracranial Aneurysms Investi-
gators. Unruptured intracranial aneurysms–risk of rupture and risks
of surgical intervention. N Engl J Med. 1998;339:1725-1733.
23. Raymond J, Guillemin F, Proust F, et al. Unruptured Intracranial
Aneurysms. A Critical Review of the International Study of Unrup-
tured Intracranial Aneurysms (ISUIA) and of Appropriate Methods
to Address the Clinical Problem. Interv Neuroradiol. 2008;14:85-96.
24. Mackey J, Brown RD Jr, Moomaw CJ, et al. Familial intra-
cranial aneurysms: is anatomic vulnerability heritable? Stroke.
2013;44:38-42.
25. Woo D, Hornung R, Sauerbeck L, et al. Age at intracranial aneu-
rysm rupture among generations: Familial Intracranial Aneurysm
Study. Neurology. 2009;72:695-698.
26. Greving JP, Wermer MJ, Brown RD Jr, et al. Development of the
PHASES score for prediction of risk of rupture of intracranial aneu-
rysms: a pooled analysis of six prospective cohort studies. Lancet
Neurol. 2014;13:59-66.
27. Juvela S, Poussa K, Lehto H, et al. Natural history of unrup-
tured intracranial aneurysms: a long-term follow-up study. Stroke.
2013;44:2414-2421.
28. Backes D, Vergouwen MD, Tiel Groenestege AT, et al. PHASES
Score for Prediction of Intracranial Aneurysm Growth. Stroke.
2015;46:1221-1226.
29. Cebral JR, Castro MA, Burgess JE, et al. Characterization of cerebral
aneurysms for assessing risk of rupture by using patient-specific
computational hemodynamics models. AJNR Am J Neuroradiol.
2005;26:2550-2559.
30. Dhar S, Tremmel M, Mocco J, et al. Morphology parameters
for intracranial aneurysm rupture risk assessment. Neurosurgery.
2008;63:185-196, discussion 196-197.
31. Lall RR, Eddleman CS, Bendok BR, et al. Unruptured intracranial
aneurysms and the assessment of rupture risk based on anatomical
and morphological factors: sifting through the sands of data. Neu-
rosurg Focus. 2009;26:E2.
32. Sadatomo T, Yuki K, Migita K, et al. Evaluation of relation among
aneurysmal neck, parent artery, and daughter arteries in middle
cerebral artery aneurysms, by three-dimensional digital subtraction
angiography. Neurosurg Rev. 2005;28:196-200.
33. Locksley HB. Natural history of subarachnoid hemorrhage, intra-
cranial aneurysms and arteriovenous malformations. J Neurosurg.
1966;25:321-368.
34. Cianfoni A, Pravata E, De Blasi R, et al. Clinical presentation of
cerebral aneurysms. Eur J Radiol. 2013;82:1618-1622.
35. Hunt WE, Hess RM. Surgical risk as related to time of intervention
in the repair of intracranial aneurysms. J Neurosurg. 1968;28:14-20.
36. Sano H, Inamasu J, Kato Y, et al. Modified world federation of
neurosurgical societies subarachnoid hemorrhage grading system.
Surg Neurol Int. 2016;7:S502-S503.
37. Hacein-Bey L, Provenzale JM. Current imaging assessment and
treatment of intracranial aneurysms. AJR Am J Roentgenol. 2011;
196:32-44.
38. Uysal E, Yanbuloglu B, Erturk M, et al. Spiral CT angiography in
diagnosis of cerebral aneurysms of cases with acute subarachnoid
hemorrhage. Diagn Interv Radiol. 2005;11:77-82.
39. Fifi JT, Meyers PM, Lavine SD, et al. Complications of modern
diagnostic cerebral angiography in an academic medical center. J
Vasc Interv Radiol. 2009;20:442-447.
40. van Gijn J, van Dongen KJ. Computed tomography in the diagnosis
of subarachnoid haemorrhage and ruptured aneurysm. Clin Neurol
Neurosurg. 1980;82:11-24.
41. Boesiger BM, Shiber JR. Subarachnoid hemorrhage diagnosis by
computed tomography and lumbar puncture: are fifth generation
263.e2 PART 3 Vascular Neurosurgery
CT scanners better at identifying subarachnoid hemorrhage? J Emerg
Med. 2005;29:23-27.
42. Kassell NF, Torner JC, Jane JA, et al. The International Cooperative
Study on the Timing of Aneurysm Surgery. Part 2: Surgical results.
J Neurosurg. 1990;73:37-47.
43. Kassell NF, Torner JC, Haley EC Jr, et al. The International Coop-
erative Study on the Timing of Aneurysm Surgery. Part 1: Overall
management results. J Neurosurg. 1990;73:18-36.
44. Whitfield PC, Kirkpatrick PJ. Timing of surgery for aneurys-
mal subarachnoid haemorrhage. Cochrane Database Syst Rev.
2001;(2):CD001697.
45. Kassell NF, Torner JC, Adams HP Jr. Antifibrinolytic therapy in
the acute period following aneurysmal subarachnoid hemorrhage.
Preliminary observations from the Cooperative Aneurysm Study. J
Neurosurg. 1984;61:225-230.
46. Pearl JD, Macdonald RL. Vasospasm after aneurysmal subarach-
noid hemorrhage: need for further study. Acta Neurochir Suppl.
2008;105:207-210.
47. Frontera JA, Claassen J, Schmidt JM, et al. Prediction of symptom-
atic vasospasm after subarachnoid hemorrhage: the modified fisher
scale. Neurosurgery. 2006;59:21-27, discussion 21-27.
48. Pluta RM, Hansen-Schwartz J, Dreier J, et al. Cerebral vasospasm
following subarachnoid hemorrhage: time for a new world of
thought. Neurol Res. 2009;31:151-158.
49. Yasuda SU, Tietze KJ. Nimodipine in the treatment of subarachnoid
hemorrhage. DICP. 1989;23:451-455.
50. Wermer MJ, van der Schaaf IC, Algra A, et al. Risk of rupture
of unruptured intracranial aneurysms in relation to patient and
aneurysm characteristics: an updated meta-analysis. Stroke. 2007;
38:1404-1410.
51. Villablanca JP, Duckwiler GR, Jahan R, et al. Natural history of
asymptomatic unruptured cerebral aneurysms evaluated at CT angi-
ography: growth and rupture incidence and correlation with epide-
miologic risk factors. Radiology. 2013;269:258-265.
52. Kailasnath P, Dickey P. ISUIA-II: the need to share more data. Surg
Neurol. 2004;62:95.
53. Johnston SC, Dudley RA, Gress DR, et al. Surgical and endo-
vascular treatment of unruptured cerebral aneurysms at university
hospitals. Neurology. 1999;52:1799-1805.
54. Johnston SC, Zhao S, Dudley RA, et al. Treatment of unruptured
cerebral aneurysms in California. Stroke. 2001;32:597-605.
55. Connolly ES Jr, Solomon RA. Management of symptomatic and
asymptomatic unruptured aneurysms. Neurosurg Clin N Am.
1998;9:509-524.
56. Raymond J, Chagnon M, Collet JP, et al. A randomized trial on
the safety and efficacy of endovascular treatment of unruptured
intracranial aneurysms is feasible. Interv Neuroradiol. 2004;10:
103-112.
57. Brilstra EH, Rinkel GJ, van der Graaf Y, et al. Treatment of intra-
cranial aneurysms by embolization with coils: a systematic review.
Stroke. 1999;30:470-476.
58. Goddard AJ, Annesley-Williams D, Gholkar A. Endovascular man-
agement of unruptured intracranial aneurysms: Does outcome
justify treatment? J Neurol Neurosurg Psychiatry. 2002;72:485-490.
Downloaded for John Egbuji (johnegbuji@gmail.com) at University of Otago from ClinicalKey.com.au by Elsevier on November 08, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
59. Raftopoulos C, Mathurin P, Boscherini D, et al. Prospective analysis
of aneurysm treatment in a series of 103 consecutive patients when
endovascular embolization is considered the first option. J Neurosurg.
2000;93:175-182.
60. Gonzalez N, Murayama Y, Nien YL, et al. Treatment of unruptured
aneurysms with GDCs: clinical experience with 247 aneurysms.
AJNR Am J Neuroradiol. 2004;25:577-583.
61. Hayakawa M, Murayama Y, Duckwiler GR, et al. Natural history of
the neck remnant of a cerebral aneurysm treated with the Guglielmi
detachable coil system. J Neurosurg. 2000;93:561-568.
62. Malisch TW, Guglielmi G, Vinuela F, et al. Intracranial aneurysms
treated with the Guglielmi detachable coil: midterm clinical results in
a consecutive series of 100 patients. J Neurosurg. 1997;87:176-183.
63. Steklacova A, Bradac O, Charvat F, et al. “Clip first” policy in
management of intracranial MCA aneurysms: single-centre experi-
ence with a systematic review of literature. Acta Neurochir (Wien).
2016;158:533-546, discussion 546.
64. Piotin M, Blanc R, Spelle L, et al. Stent-assisted coiling of intra-
cranial aneurysms: clinical and angiographic results in 216 consecu-
tive aneurysms. Stroke. 2010;41:110-115.
65. Benitez RP, Silva MT, Klem J, et al. Endovascular occlusion of wide-
necked aneurysms with a new intracranial microstent (Neuroform)
and detachable coils. Neurosurgery. 2004;54:1359-1367, discussion
1368.
66. Spiotta AM, Wheeler AM, Smithason S, et al. Comparison of tech-
niques for stent assisted coil embolization of aneurysms. J Neuroin-
terv Surg. 2012;4:339-344.
67. Eller JL, Dumont TM, Sorkin GC, et al. The Pipeline emboliza-
tion device for treatment of intracranial aneurysms. Expert Rev Med
Devices. 2014;11:137-150.
68. Nelson PK, Lylyk P, Szikora I, et al. The pipeline embolization
device for the intracranial treatment of aneurysms trial. AJNR Am J
Neuroradiol. 2011;32:34-40.
69. Becske T, Potts MB, Shapiro M, et al. Pipeline for uncoilable or
failed aneurysms: 3-year follow-up results. J Neurosurg. 2016;1-8.
70. Becske T, Kallmes DF, Saatci I, et al. Pipeline for uncoilable or
failed aneurysms: results from a multicenter clinical trial. Radiology.
2013;267:858-868.
71. Molyneux AJ, Kerr RS, Yu LM, et al. International subarachnoid
aneurysm trial (ISAT) of neurosurgical clipping versus endovascu-
lar coiling in 2143 patients with ruptured intracranial aneurysms:
a randomised comparison of effects on survival, dependency, sei-
zures, rebleeding, subgroups, and aneurysm occlusion. Lancet.
2005;366:809-817.
72. McDougall CG, Spetzler RF, Zabramski JM, et al. The Barrow
Ruptured Aneurysm Trial. J Neurosurg. 2012;116:135-144.
73. Darsaut TE, Raymond J. Barrow Ruptured Aneurysm Trial: 3-year
results. J Neurosurg. 2013;119:1642-1644.
74. Spetzler RF, McDougall CG, Zabramski JM, et al. The Barrow Rup-
tured Aneurysm Trial: 6-year results. J Neurosurg. 2015;123:609-617.
75. Johnston SC, Dowd CF, Higashida RT, et al. Predictors of rehemor-
rhage after treatment of ruptured intracranial aneurysms: the Cere-
bral Aneurysm Rerupture After Treatment (CARAT) study. Stroke.
2008;39:120-125.