REVIEWS

Unruptured intracranial aneurysms:

development, rupture and preventive
management
Nima Etminan­1 and Gabriel J. Rinkel2
Abstract | Saccular unruptured intracranial aneurysms (UIAs) have a prevalence of 3% in the adult
population, and are being increasingly detected because of improved quality and higher
frequency of cranial imaging. Large amounts of data, providing varying levels of evidence, have
been published on aneurysm development, progression and rupture, but less information is
available on the risks and efficacy of preventive treatment. When deciding how to best manage
UIAs, clinicians must consider the age and life expectancy of the patient, the estimated risk of
rupture, the risk of complications attributed to preventive treatment, and the level of anxiety
caused by the awareness of having an aneurysm. This Review highlights the latest human data on
the formation, progression and rupture of intracranial aneurysms, as well as risks associated with
preventive treatment. Considering these we discuss the implication for clinical management.
Furthermore, we highlight pivotal questions arising from current data on intracranial aneurysms
and the implications the data have for future experimental or clinical research. We also discuss
data on novel radiological surrogates for rupture for those aneurysms that do not require
preventive occlusion. Finally, we provide guidance for clinicians who are confronted with patients
with incidentally detected UIAs.

1
Department of
Neurosurgery, University
Hospital Mannheim,
Theodor-Kutzer-Ufer 1–3,
Medical Faculty,
University of Heidelberg,
68167 Mannheim, Germany.
2
Brain Center Rudolf Magnus,
Department of Neurology and
Neurosurgery, University
Medical Centre Utrecht,
Heidelberglaan 100,
3584CX, Utrecht,
Netherlands.
Correspondence to N.E.
nima.etminan@umm.de
doi:10.1038/nrneurol.2016.150
Published online 3 Nov 2016
Saccular unruptured intracranial aneurysms (UIAs) are
pathological dilations at major branching brain arteries
that affect 3–5% of the adult population, irrespective of
geographical location or ethnicity1,2. Intracranial aneu‑
rysms typically develop after the second decade of life
— most often between the fourth and sixth decade —
and are more prevalent in women than in men 2–4.
Approximately 20–30% of patients with UIAs harbour
more than one aneurysm5.
Concomitant to improvements that have been
made in the quality of intracranial imaging technol‑
ogies, the application of MRI and CT as diagnostic
tools has increased over the past two decades6,7. As a
consequence, UIAs are more frequently detected, and
clinicians are increasingly confronted with a dilemma
regarding the choice of adequate clinical management,
namely, preventive treatments (endovascular or sur‑
gical aneurysm repair) with inherent risks of compli‑
cations, or conservative management with or without
follow‑up imaging, which leaves patients at a small
but definite risk of aneurysm rupture. Rupture of an
intracranial aneurysm results in subarachnoid haemor­
rhage (SAH), which has a poor outcome in up to 35%
of patients8.
The pathogenesis of UIAs has implications for treat‑
ment, as well as for the design of future clinical or experi­
mental studies on UIAs. An important point to note is
that non-saccular aneurysms have a unique pathogenesis,
and are managed in a different manner from saccular
aneurysms9. The same holds true for UIAs in children.
Fewer than 5% of patients with UIAs are children, and
the risk factors and mechanisms of formation differ
substantially between children and adults. In children,
50–70% of UIAs are caused by trauma, infection or dis‑
sections, only 20–30% have a saccular shape, and the
majority are clinically symptomatic10.
The distinct uncertainty surrounding the treatment
of UIAs is a consequence of conflicting data on aneu‑
rysm pathogenesis and risk of rupture, and has resulted
in large variations in the management of patients with
UIAs7,11. The most recent guidelines on the manage‑
ment of these patients, formulated by the American
Heart Association, have provided some clarity, but
uncertainties remain12,13.
In this Review, we will outline the current human
data on aneurysm formation, progression and rupture.
In particular, we will describe the clinical management
of patients with UIAs, highlight the areas of uncertainty,

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Key points aneurysm than do non-smokers25. Furthermore, the

overall risk of intracranial aneurysm formation is twofold
• Up to 3% of the general population carries an unruptured intracranial aneurysm (UIA) higher in females than in males20,29,30.
• Uncritical preventive aneurysm repair carries disproportionate risks of complications, Although evidence suggests that individuals with a
whereas uncritical conservative management with or without follow‑up imaging family history of intracranial aneurysms or SAH are at
leaves patients at a small but definite risk of aneurysm rupture increased risk of formation of an intracranial aneurysm,
• The decision of how best to manage patients with UIAs is based on several factors, no specific genes strongly associated with formation
including patient age, risk of rupture and treatment, and level of anxiety related have yet been identified. A meta-analysis comprising
to diagnosis data from 61 candidate gene association or genome-
• A better understanding is required of the magnitude of risk of rupture associated with wide association studies, which included 32,887 sporadic
factors such as smoking and aneurysm morphology aneurysms and 83,683 controls, identified three single
• More-robust data are needed on the risks and efficacy of endovascular versus surgical nucleotide polymorphisms (SNPs) that were associated
preventive aneurysm repair with the presence of sporadic intracranial aneurysms.
• Future studies should address the role of risk factor modification, including smoking These variants all resided in loci that harbour common
cessation and treatment of hypertension, as well as anti-inflammatory drugs as polymorphisms related to increased incidence of cardio­
treatments for unruptured aneurysms that do not require preventive repair vascular structural deficiencies and diseases. The SNPs
were located on chromosome 9 within the CDKN2B‑AS1
gene, on chromosome 8 near the SOX17 transcription
and pose questions for future experimental or clinical regulator gene, and on chromosome 4 near the endothe‑
Non-saccular aneurysms research. We focus solely on asymptomatic saccular UIAs lin receptor gene31. Subsequent genome-wide association
Aneurysms that are fusiform in in the adult population: we do not discuss non-­saccular studies32–34 have found additional loci on chromo‑
shape and involve the parent intracranial aneurysms or UIAs that develop in children. some 7 near HDAC9, as well as in chromosomal regions
vessel wall circumferentially.
1p34.3–p36.13, 19q13.3, Xp22 and 7q11. The strongest
Saccular aneurysms Formation of intracranial aneurysms evidence for linkage was with a locus on 7q11 near the
Aneurysms that bulge out at a Intracranial aneurysm formation is an incompletely gene that encodes elastin, a protein that is involved in
cerebral artery bifurcation and under­stood, gradual process. According to our cur‑ the preservation of vessel wall integrity. The genome-
contain a distinct neck where
rent under­standing, detrimental haemodynamic fac‑ wide association data remain to be related to the intra­
they attach to the parent
vessel(s). tors, such as haemodynamic stress and vascular risk cranial aneurysm phenotype, and need to be validated
factors (including hypertension, lipid accumulation, in larger aneurysm cohorts in the general population.
Haemodynamic stress arterio­sclerosis and smoking), along with a genetic pre­
Stress that is placed on the disposition, are all involved in the process of aneurysm Structural changes and haemodynamics
vessel wall by the flow of
blood and its corpuscular
formation14–17 (BOX 1). The walls of cerebral arteries are structurally distinct
components. UIAs are not a congenital disorder, but develop over from those of extracranial arteries, in that they have a
the life course, and are extremely rare in patients under sparse tunica adventitia and a lower proportion of elas‑
Hypertension 20 years of age3. The likelihood of a UIA is increased in tic fibres. Moreover, cerebral arteries are immersed in
In the context of this Review,
people with a first-degree relative diagnosed with an the cerebrospinal fluid of the subarachnoid space rather
hypertension, whether treated
or untreated, is defined as a intracranial aneurysm or SAH (prevalence ratio (PR) than in connective tissue3,35,36 (BOX 1). These structural
positive risk factor when the 3.4, 95% CI 1.9–5.9), or autosomal dominant poly­ factors are thought to make cerebral arteries susceptible
systolic blood pressure is cystic kidney disease (PR 6.9, 95% CI 3.5–14.0), com‑ to aneurysm formation.
>140 mmHg. pared with reference populations2,18–20. Connective In the wall of a healthy cerebral artery, the internal
Smoking
tissue disorders are often cited as risk factors for aneu‑ lamina maintains the elasticity and structural integrity of
In the context of this Review, rysm forma­tion, although no sound studies exist that the vessel wall at an arterial bifurcation37,38. Degeneration
smoking is defined as a positive support this ­association, and several studies negate such or disruption of the internal elastic lamina at a bifurca‑
risk factor for unruptured an association21–23. tion is a key event in the formation of an intracranial
intracranial aneurysm rupture if
The true incidence of sporadic intracranial aneurysm aneurysm. The definite cause of the degeneration and
adults have smoked 100
cigarettes in their lifetime or formation and relative importance of risk factors (TABLE 1) why it only occurs in certain individuals, however,
smoke cigarettes (either daily are difficult to capture. Most data on intra­cranial aneu‑ remains unclear.
or non-daily) at the time of rysm formation are derived from patients with previous Anatomical variations in the circle of Willis are con‑
clinical presentation. SAH from a different aneurysm — a subpopulation sidered to be an important factor in intra­cranial aneu‑
Tunica adventitia
that is hypothesized to be prone to develop additional rysm formation36,39. Following a cohort study on people
The outermost tunica layer of aneurysms compared with the general population24–28. with a familial preponderance to saccular intracranial
a blood vessel surrounding the In this population, the annual rate of de novo aneurysm aneurysms, investigators reported that bifurcations
tunica media. The tunica ­formation is reported to range from 0.2–1.8%24–28. comprising hypoplastic branching arteries or bifurca‑
adventitia predominantly
tions with particularly sharp angles were risk factors for
contains collagen type I and
embeds a vessel into Genetic factors aneurysm formation. The researchers concluded that
surrounding tissue. Cerebral The formation of intracranial aneurysms is influenced by the increase in associated risk was possibly attributable
arteries do not display a a complex interplay between genetic and environmen‑ to altered haemodynamic flow conditions caused by
meaningful tunica adventitia, tal risk factors, and the two might even reinforce each anatomical variations40. Flow towards and within sac‑
which is often discussed as a
structural prerequisite for
other25. For example, among individuals with a positive cular intracranial aneurysms is an important contribu‑
intracranial aneurysm family history of intracranial aneurysms, smokers have tor to aneurysm development and is a determinant for
formation. a threefold higher risk of harbouring an intra­cranial structural instability.

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Box 1 | Structural and molecular pathogenesis of intracranial aneurysms

Panel a illustrates the anterior communicating artery (AComA) complex,
filling from the left (dominant) anterior cerebral arterior (A1) and, to a
lesser extent, from the hypoplastic right A1 — a variation typically found in
AComA aneurysms. Inset i shows the ultrastructural composition of a
cerebral artery. The luminal side of a cerebral artery consists of a layer of
endothelial cells (ECs) that are connected by tight junctions. Abluminal to
the EC layer is a thin basement membrane (BM), which is positioned
between the EC layer and a thick internal elastic lamina (IEL) with elastin
fibres. An organized network of vascular smooth muscle cells (SMCs)
comprise the tunica media. The most abluminal layer is a thin tunica
adventitia, which contains fibroblasts (FBs) and white blood cells (WBC)3,35.
The anatomical variation, structural composition and physiological
homeostasis of a cerebral artery wall might be affected by risk factors for
intracranial aneurysm development, such as smoking and hypertension, all
of which result in aberrant blood flow. In response to these risk factors,
structural changes occurring in the wall of cerebral arteries result in
disruption of the IEL at the arterial bifurcation (panel b and inset ii)14–16,30,43.
Aberrant blood flow leads to mechanical overload and shift in tensile
forces, which results in reconstitution and degradation of the extracellular
matrix through apoptosis and/or modulation of smooth muscle cells, as
well as dysfunction of endothelial cells and influx of macrophages39,55–57.
The detrimental processes acting on the artery wall are further
exacerbated by cellular and humoral inflammatory responses,
predominantly regulated via activation of tumour necrosis factor,
monocyte chemoattractant protein‑1, IL‑1β, NF‑κB, matrix
metalloproteinases, and cyclooxygenase‑1 and cyclooxygenase‑2
(REFS 53,58,76). Blood inflow and impingement exposes the structurally
defected arterial to high wall shear stress, resulting in aneurysm sac
formation (panel c). The aneurysmal sac continues to grow until ongoing
vessel wall repair and extracellular matrix degradation reach a balance
(panel d)39. The main molecular constituent of the aneurysm wall is collagen
(inset iii). The main cellular components in the aneurysm wall are SMCs, a
discontinuous layer of ECs and a minor proportion of inflammatory cells,
such as macrophages, neutrophils and lymphocytes3,16,37,121,122.

i ii

FB

SMCs

WBCs

IEL
BM
Lumen ECs Lumen

A2

a
A1
b
A2 AComA

A1

Risk factors +
aberrant hemodynamics
Internal
carotid artery

d
c

iii

FB

SMCs
WBCs

ECs

Lumen

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Table 1 | Risk factors for aneurysm formation

Risk factor Increase in risk Cohort size Study type Population References
(95% CI in brackets)
Smoking OR 4.07 (1.09–15.15)*‡ 87 patients with unruptured Prospective cohort Finnish 24
intracranial aneurysms
OR 3.0 (2.0–4.5)§ 206 patients with previous SAH Case–control White, non-Finnish 25
from an earlier aneurysm
HR 3.8 (1.5–9.4) 610 patients with previous SAH Prospective cohort White, non-Finnish 27
from a different aneurysm
HR 5.61 (2.86–11.1)* 1,419 patients with a previous Prospective cohort Finnish 28
SAH from a different aneurysm
Hypertension HR 2.3 (1.1–4.9)§ 610 patients with previous SAH Prospective cohort White, non-Finnish 25,27
from a different aneurysm
OR 2.9 (1.9–4.6)* 206 patients with previous SAH Case–control White, non-Finnish
from a different aneurysm
Concomitant smoking OR 8.3 (4.5–15.2) 206 patients with previous SAH Case–control White, non-Finnish 25
and hypertension from a different aneurysm
Family history for stroke OR 1.6 (1.0–2.5)* 206 patients with previous SAH Case–control White, non-Finnish 25
other than SAH from a different aneurysm
Positive familial history HR 2.7 (1.0–7.4) 610 patients with previous SAH Prospective cohort White, non-Finnish 27
for aneurysm from a different aneurysm
Multiple aneurysms HR 3.2 (1.2–8.6)§ 610 patients with previous SAH Prospective cohort White, non-Finnish 27
from a different aneurysm
Female sex OR 4.73 (1.16–19.38)*‡ 87 patients with unruptured Prospective cohort Finnish 24
intracranial aneurysms
*Multivariate analysis. ‡Age-adjusted. §Aneurysm formation and progression combined. SAH, subarachnoid haemorrhage.

Myointimal hyperplasia
Translocation and proliferation
of vascular smooth muscle cells
in response to endothelial injury
with thickening of the luminal
aspect of the vessel wall.
Patient-specific or idealized computational
f­ luid-dynamic models derived from angiographic
data are increasingly used to model flow dynamics
in aneu­r ysms 41–45. Fluid-dynamic models calculate
and visualize wall shear stress or wall shear gradients,
intra­-aneurysmal flow, impingement zones, and flow
patterns or velocities. Wall shear stress constitutes the
degree of friction in the intracranial aneurysm wall that
results from blood inflow and impingement into the
aneurysm. High and low wall shear stress can both be
present during aneurysm formation but the relevance
of these flow conditions to the pathogenesis, growth
and rupture of an aneurysm remain unclear39.
Data generated from fluid-dynamic models could
help improve our understanding of aneurysm forma‑
tion patterns and potential structural deficiencies in
aneurysms. The relevance of existing data derived from
computational fluid modelling is limited, however,
because the majority of studies compared ruptured with
unruptured aneurysms. An ideal — albeit i­dealistic —
approach would be to compare the same aneurysm
before and after rupture42,46–51. Moreover, most of the
simulations remain purely mathematical, with limited
integration of actual biological data. For an accurate
simulation, biologically relevant readings, such as intra-­
aneurysmal blood pressure gradients or aneurysm wall
elasticity and tension, need to be included.
Molecular changes
In response to internal elastic lamina disruption and
the subsequent mechanical overload and shift in ten‑
sile forces (BOX 1), vascular smooth muscle cells and
fibroblasts synthesize collagen types I and V, which are
the main molecular constituents of intracranial aneu‑
rysms16,52. Vascular smooth muscle cells, which perform
contractile functions in the vessel wall, might initially
migrate into the tunica intima in response to endo­
thelial injury. The change in the physiological locality
and phenotype of the vascular smooth muscle cells
towards the synthetic type could contribute to vessel
wall repair through collagen synthesis, resulting in myo-
intimal hyperplasia. Moreover, sustained haemodynamic
shear stress on the vascular wall leads to reconstitution
and degradation of the extracellular matrix, dysfunction
of endothelial cells, and apoptosis or phenotypic modu‑
lation of smooth muscle cells towards dedifferentiated,
proinflammatory smooth muscle cells.
Once the molecular mechanisms fail to compen‑
sate for the mechanical overload of the vessel wall and
myointimal injury, cellular and humoral inflamma‑
tory responses become the main drivers of aneurysm
formation16,53,54 (BOX 1). These responses, which are
mediated by inflammatory cytokines such as tumour
necrosis factor (TNF), IL‑1β and matrix metallopro‑
teinases (MMPs), promote influx of macrophages and
­continuous ­degradation of collagen and elastin fibres55–58.
Wall shear stress might also contribute to cellular
inflammatory responses during aneurysm formation.
High wall shear stress and/or impinging blood flow
contribute to the formation and growth of aneurysms
via mural cell-mediated destructive wall remodelling,
and are suggested to lead to rather small, thin-walled
aneurysms. Low wall shear stress is assumed to result
in destructive, inflammation-mediated wall remodelling

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due to recirculating or disturbed intra-aneurysmal blood
flow, and is suggested to lead to comparatively large,
thick-walled artherosclerotic aneurysms39. As indicated
above, low and high wall shear stress can coexist within
one aneurysm, but the implications of these flow con‑
ditions and resulting aneurysm subtypes for aneurysm
rupture risk remain unclear.
Aneurysm progression and rupture
Aneurysm growth
UIAs can remain unchanged for a long time before
undergoing episodes of rapid growth, during which they
are more prone to rupture59–61 (TABLE 2). Mathematical
simulations derived from prospective aneurysm cohort
studies and data from molecular analy­sis of human aneu‑
rysms suggest that aneurysm growth is discontinuous
and stochastic rather than linear3,62–64 (BOX 2). It should
be realized that not all aneurysms have a long life; some
develop and rupture within a short period of time, that is,
within weeks or months (FIG. 1). In one cohort study of 458
people with familial risk of aneurysms, one patient devel‑
oped an SAH from a de novo aneurysm just 3 years after a
negative magnetic resonance angiogram29. Furthermore,
several case reports of patients who survived a previous
SAH from a different aneurysm have described the rup‑
turing of de novo aneurysms within intervals as short as
weeks or months following a clear scan65–69.
Numerous cohort studies have described rates
of aneurysm growth over different time intervals in
patients with UIAs24,26–28 (FIG. 2; TABLE 2). Furthermore,
in an analysis of 557 patients from three prospective
unruptured aneurysm cohorts, 12% of the 734 UIAs
included in the analysis demonstrated growth during
follow‑up (mean duration 2.7 years). The risk of rupture
in this pooled analysis was 12‑fold higher in growing
aneurysms than in stable aneurysms59. In a meta-­analysis
including data from 3,990 patients with 4,972 unrup‑
tured aneurysms, 437 (9%) of the UIAs enlarged over a
mean follow‑up duration of 2.8 years70. These findings
underline the necessity of follow‑up for conservatively
managed patients with UIAs.
Changes during growth and rupture
Aneurysm growth is reflected in radiological — and, thus,
macroscopic — change, but structural changes also occur
at the microscopic and molecular levels. Existing radio‑
logical imaging methods used in clinical practice can only
capture macroscopic structural changes. Consequently,
clinicians and researchers are presented with a problem,
as potentially meaningful structural changes that occur
beyond the macroscopic level remain undetected dur‑
ing routine follow-up. With a view to addressing this
issue, researchers are increasingly investigating novel
techniques to analyse the structural changes that occur
at the molecular level in UIAs. In one such study, radio­
carbon birth dating of collagen type I, the main molecu‑
lar constituent of aneurysms, was used as an indicator for
molecular change3,4. The investigators reported that col‑
lagen turn­over and remodelling was notably accelerated
in aneurysms from people who smoked or had arterial
hypertension. The age of collagen type I in the aneurysms
did not correlate with aneurysm size, location, morphol‑
ogy, or rupture status3. The data from the study indicate
that cerebral aneurysms are not congenital, and they
undergo ongoing structural change, which is accelerated
in patients with cardiovascular risk factors.
Aneurysm wall inflammation. An increasing body of
studies is highlighting a pivotal role for aneurysm wall
inflammation in aneurysm growth and rupture58,71,72.
Since 2012, several studies have investigated the relation­
ship between aneurysm wall inflammation and aneu‑
rysm stability. Most of the studies have utilized MRI
contrast enhancement in or around the aneurysm wall,
which is hypothesized to highlight areas of inflam‑
mation. In a prospective study of a total of 108 UIAs
in 87 patients, circumferential aneurysm wall inflam‑
mation, as visualized by MRI, was related to aneurysm
growth or rupture73. In another prospective study of
22 patients with a total of 30 UIAs, investigators used
­ferumoxytol-enhanced MRI to visualize macrophages
in the aneurysm wall as markers of inflammation. The
investigators reported that seven of the 30 UIAs analysed
in the study showed early ferumoxytol uptake, indicating
raised levels of inflammation in the aneurysm wall. The
findings were confirmed with subsequent histological
analyses in four of the aneurysms following rupture.
The remaining three aneurysms that showed early
ferumoxytol uptake were managed conservatively and
ruptured within 6 months of the initial imaging71. These
data underline that early ferumoxytol uptake in UIAs is
indicative not only of aneurysm wall inflammation, but
also of aneurysm instability.
Further evidence supporting a role for inflamma‑
tion in the rupture of aneurysms was provided by a post
hoc analysis of a nested control study of patients with
UIAs who were using anti-inflammatory medications.
In this study, use of acetylsalicylic acid (aspirin) more
than three times a week significantly reduced the chance
of aneurysm rupture72. These data have been corrobo‑
rated by subsequent imaging studies investigating the
association between aneurysm wall inflammation and
aneurysm rupture74,75. In a phase I, randomized study of
11 patients74, aspirin treatment reduced aneurysm wall
Table 2 | Risk factors for aneurysm growth19,24,59,88
Risk factor Risk ratio 95% CI
Smoking 2.2–3.9* Not reported
Female sex 3.3 1.1–10
Hypertension 2.3 1.1–4.9
Initial aneurysm size 1.1‡ 0.8–1.5
2.56 §
1.93–3.39
Multiple aneurysms 2.04 1.56–2.66
Multilobed aneurysm 2.9 1.0–8.5
Oblonged aneurysm 2.4 1.0–5.8
Posterior circulation 2.0 0.6–7.0
*Range over several studies. ‡Per mm increase in size.
§
Compared with aneurysms </=4 mm.

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inflammation, as measured by ferumoxytol-enhanced Molecular changes. At the molecular level, aneu‑

MRI. Following the trial, aspirin treatment reduced rysm stability is dependent on a balance between
radiological and histological indicators of aneurysm two competing process: aneurysm wall repair via
wall inflammation. eutrophic collagen turnover, vascular smooth muscle

Box 2 | Intracranial aneurysm progression and rupture

Whether an aneurysm (panel a) will remain structurally stable (panel b)
or grow (panel c) is thought to depend on a balance between
aneurysm wall repair and destruction12,39. Over time, aneurysms
undergo stochastic episodes of either structural stability or growth
(inset i). During periods of growth intracranial aneurysms are more
prone to rupture59,64,70. As inset ii shows, when the ages of patients
(blue lines) are plotted on a graph along with the age of aneurysm
collagen samples, which are derived from radiocarbon dating of
atmospheric F14C (black line), it becomes evident that unruptured
intracranial aneurysms (red lines) are typically ≤5 years old,
irrespective of patient age or aneurysm-related features3. This finding
suggests that irrespective of radiological stability, aneurysms undergo
ongoing structural change at the molecular level, which is notably
accelerated in patients who smoke or are hypertensive. Under further
exposure to risk factors for aneurysm growth or rupture, including
hypertension, smoking and aneurysm wall inflammation, and/or
aberrant haemodynamics, the ongoing detrimental molecular change
might result in aneurysm growth and morphological change (panel d
and inset iii)16,37,39,54,76,77,122, which are surrogates for rupture. At the
molecular level, dysfunction or apoptosis of endothelial cells (ECs) and
vascular smooth muscle cells (SMCs) promotes inflammatory
responses in the intracranial aneurysm wall, resulting in leukocyte
infiltration16,37,74,78,79, which can ultimately result in aneurysm rupture
(panel e).

i 1.8 ii
Growth and/or rupture
Aneurysm size

1.6
a Stable

F14C
1.4

1.2

1.0

Time 1920 1940 1960 1980 2000 2020

Year

Stable b

Growth
and/or
e rupture

Risk factors +
aberrant hemodynamics
c

iii WBCs

FB

Thrombus
d SMCs

Lumen ECs
FB, fibroblast; WBC, white blood cell.

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Time

Figure 1 | Proposed scenarios for aneurysm formation, progression and rupture. According NaturetoReviews
cohort studies
| Neurology
and biomolecular and pathophysiological studies of human intracranial aneurysms, an intracranial aneurysm can have
various outcomes. a | Stochastic episodes of growth until rupture. b | Long-term structural stability followed by growth
without rupture. c | Long-term stability followed by rupture without any growth. d | Even very small intracranial
aneurysms can develop rapidly and subsequently rupture, without any intervening period of stability. These different
scenarios highlight the difficulty of accurately predicting the outcome after aneurysm formation, and the need for
better surrogates for the outcome.

cell proliferation and regeneration of the extracellu‑
lar matrix, and aneurysm wall destruction caused by
dystrophic collagen turnover and degradation of the
extracellular matrix (BOX 1; BOX 2)12,39. The structural
integrity of a UIA can fail when the destructive events
outcompete the constructive events.
The destructive events that result in the rupture
of a UIA are mediated by aberrant-flow-induced dys‑
function or apoptosis of endothelial cells, thrombus
formation, smooth muscle cell dysfunction, and pro‑
teolysis or degradation of the extracellular matrix16,37.
Humoral and cellular inflammatory responses within
the wall of the aneurysm, which are mediated by TNF,
monocyte chemoattractant protein‑1, IL‑1β, NF‑κB and
MMPs, are triggered by these destructive events54,58,76–80.
Moreover, evidence from gene expression studies points
to lysosomal degradation as well as other destructive
immune responses in the aneurysm wall as important
factors that facilitate aneurysmal rupture80.
The exact molecular mechanisms and inflammatory
mediators that ultimately cause aneurysm rupture are
still uncertain. Histological assessment of aneurysms
that were defined as ‘rupture-prone’ on the basis of
radiological examination revealed infiltration by
T cells, polymorphonuclear neutrophils and mast cells.
An imbalance between proinflammatory M1 macro­
phages and anti-inflammatory M2 macrophages was
also described, as was mural cell loss and extracellular
matrix degradation71. The key inflammatory enzymes
­c yclooxygenase‑1 (COX‑1) and ­c yclooxygenase‑2
(COX‑2), which catalyse prostaglandin synthesis from
arachidonic acid, are also thought to be important
components in the pathogenesis of aneurysm rupture.
The hypothesis is based on the findings that COX‑2
is upregulated in unruptured aneurysmal endothelial
cells, ruptured aneurysms show increased COX‑2 l­ evels
in the aneurysm wall, and inhibition of COX‑2 with
aspirin reduces histological and radiological aneurysm
wall inflammation and rupture risk74,75,81,82. Although
the presumably beneficial effects of aspirin on aneu‑
rysm wall inflammation — and, thus, aneurysm rup‑
ture risk — are interesting, the exact mechanisms that
underlie these effects remain to be further elucidated
before clinical conclusions can be drawn.

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60% temporary increase in exposure to risk factors, such as

a sudden rise in blood pressure92–94. Systemic infections
might also be involved in the rupture of UIAs; a notion
50%
that is supported by the finding that SAH incidence is
increased during and shortly after influenza epidemics95.
Risk of aneurysm growth

40% A number of established risk factors that contrib‑

30%
20%
10%
0%
1 2 9 19
Follow-up time (years)
Figure 2 | Risk of aneurysm growth over time. The data inNature the graph were |derived
Reviews Neurology
from four different cohort studies and pooled analyses of individual patient data24–28.
Irrespective of other features such as aneurysm size, location and morphology or patient
characteristics (hypertension, smoking), the relative risk of aneurysm growth (y-axis) is
small after 1 year of follow up (x-axis), but increases significantly at 2, 9 and 19 years of
follow up. Up to 45% of aneurysms demonstrated growth over a 19-year period. The
increased risk of growth over time underlines the need for standardized and long-term
follow up, especially in patients with an untreated aneurysm who have a life expectancy
longer than 5–10 years.
Factors involved in aneurysm rupture
Risk factors for aneurysm rupture
Several prospective cohort studies have investigated
the risk of rupture in different UIA patient popula‑
tions and over different follow‑up periods83–89 (TABLE 3).
One important point to note is that the data in these
cohort studies pertain to asymptomatic UIA patients
— unruptured but symptomatic aneurysms are con‑
sidered to have a large risk of rupture and, therefore,
are often treated83,90. One major limitation of existing
data on the risk of asymptomatic UIA rupture is that
they are derived from cohort studies that focused on
selected populations. For this reason, these studies are
often referred to as aneurysm rupture risk studies rather
than natural history studies on intracranial aneurysms.
The largest meta-analysis on UIA rupture risk con‑
ducted to date comprised six cohort studies, which
included data from 8,382 patients and a total of 10,272
UIAs. The study identified six independent risk factors
for aneurysm rupture: patient age ≥70 years, a history
of hypertension, previous SAH from another aneurysm,
the size and site of the aneurysm, and the patient’s geo‑
graphical region (TABLE 3)91. The subsequently developed
PHASES score for prediction of aneurysm rupture risk
is based on these six key risk factors, and provides abso‑
lute estimates for the 5-year risk of rupture, which range
from 0.3% to ≥15% (FIG. 3).
Although UIA size is the most powerful and consist‑
ent risk factor for rupture, small aneurysms (<5 mm)
can still rupture during follow-up. Potential expla‑
nations for the rupturing of small aneurysms include
thin walls attributed to high wall shear stress, and a
ute to rupture of intracranial aneurysms could not
be included in the PHASES data set. These risk fac‑
tors were either not recorded or not homogeneously
defined across all the prospective cohort studies, so
could not be pooled and included in the PHASES pre‑
diction model (TABLE 3). For these excluded risk factors,
which can be divided into patient and aneurysm char‑
acteristics, only relative, rather than absolute, effects
can be determined.
Patient-related risk factors. Smoking is the most impor‑
tant patient characteristic not to be included in the
PHASES prediction score. Only one of the six cohort
studies used in the PHASES data set recorded data
on smoking during follow‑up89. The study, which was
based on a population of Finnish patients, had a median
follow‑up time of >20 years. The investigators reported
that current smokers were three times more likely to
experience a rupture than were patients who had never
smoked or patients who had stopped smoking89,96. The
important role of current smoking as an independent
risk factor was further underlined in a pooled analysis
of 26 prospective cohort studies on SAH risk factors97.
A family history of intracranial aneurysms is also
considered to be a strong risk factor for intracranial
aneurysm rupture. The annual UIA rupture rate is
17 times higher in patients with a family history of
intra­cranial aneurysms than in those with no such
history20,98. Furthermore, compared with the general
population, people who have two or more first-degree
relatives diagnosed with intracranial aneurysms are
four times more likely to have an aneurysm, and their
lifetime risk of SAH is increased 50‑fold29. The modest
increase in the presence of familial aneurysms but much
larger increase in the incidence of SAH from a famil‑
ial aneurysm suggests that familial aneurysms have a
higher risk of rupture.
Genetic factors might have a role not only in aneu‑
rysm formation but also in aneurysm rupture. A new
systematic review has highlighted ten genetic factors that
are associated with intra­cranial aneurysm rupture, with
varying levels of evidence (Kleinloog, R. et al. unpub‑
lished work). The reported genetic risk factors that were
associated with rupture included polymorphisms in
the genes encoding endothelial nitric oxide synthase
(also known as eNOS), complement factor H, elastin,
Jun, α-­synuclein, MMP-1 and MMP-9, an i­nterferon,
­fibronectin, and 5‑aminolevulinate synthase 2.
Aneurysm-related risk factors. The most important
established aneurysm characteristics that are associ‑
ated with aneurysm rupture and are not included in
the PHASES prediction scores are aneurysm shape or
morphology, and the direction of blood flow into the
aneurysm. Irregular aneurysm morphology, such as

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Aspect ratio
Aneurysm height divided by
neck width. An aspect ratio
greater than 1.6 is reported to
be associated with increased
rupture risk.
Size ratio
The largest aneurysm diameter
divided by parent artery
diameter. When larger than 3,
the size ratio is reported to be
associated with rupture risk.
the presence of a daughter sac, was identified as a sig‑
nificant and independent risk factor for aneurysm rup‑
ture in a large Japanese cohort study from 2012 (REF. 87).
In this study, UIAs with a daughter sac had a 1.6‑fold
increased risk of rupture compared with aneurysms
that had no daughter sac, irrespective of aneurysm size
or location. A study that assessed the characteristics of
ruptured intra­cranial aneurysms versus UIAs within
individual patients with SAH showed that oblong
aneurysms had a greater rupture risk than did spher‑
ical aneurysms99. A population-based case–control
study from Finland also found that irregular shape is
an important risk factor for rupture100. Other studies
comparing ruptured versus unruptured aneurysms
found associations between aspect ratio >1.6 or size ratio
>3 and rupture status101–103.
The angle of blood flow into the aneurysm also influ‑
ences the risk of rupture. In an analysis of 75 ruptured
intracranial aneurysms and 75 UIAs from 126 patients,
straight flow, which is blood flow directly into the aneu‑
rysm, was associated with higher risk of rupture than
were curved flow or equivalent flow104.

Table 3 | Risk factors for intracranial aneurysm rupture

Risk factor Change in risk Cohort size (number of Level of evidence Population
(95% CI in brackets) unruptured IAs unless
otherwise stated)
Patient and aneurysm factors
Hypertension91,97 HR 1.3 (1.0–1.7)* 8,382 (10,272) IIa European, North American,
Japanese and Finnish
RR 2.5 (2.0–3.1)* 306,620 (NA) IIa Australasian
Heavy alcohol use (≥150 g per week) 97
RR 2.1 (1.5–2.8)* 306,620 (NA) IIa Australasian
Smoking (current and former HR 2.4 (1.8–3.4)* 306,620 (NA) IIa Australasian
smokers combined)97
HR 2.44 (1.02–5.88)* 142 (181) IIb Finnish
Prior SAH from other aneurysm 91
HR 1.4 (0.9–2.2)* 8,382 (10,272) IIa European, North American,
and Finnish
Familial SAH (two or more 17‑fold‡ 113 (148) IIb European and North
first-degree relatives)98 American
Aneurysm growth on serial imaging59 12-fold§ 557 (734) IIa European and North
American
Irregular aneurysm morphology/ HR 1.63 (1.08–2.48) 5,720 (6,697) IIb Japanese
presence of daughter sac87,100
OR 7.1 (6.0–8.3) 4,074 (5,814 ruptured and IIc Finnish
unruptured aneurysms)
Multiple aneurysms84 HR 4.87 (1.62–14.65)* 446 (540) IIb Japanese
Size of aneurysm (mm) 91

<5.0 Reference size

5.0–6.9 HR 1.1 (0.7–1.7)*
European, North American,
7.0–9.9 HR 2.3 (1.5–3.6)* 8,382 (10,272) IIa
Japanese and Finnish
10.0–19.9 HR 5.5 (3.8–8.1)*
≥20.0 HR 20.8 (13.2–33.0)*
Aneurysm location 91

Middle cerebral artery Reference location

Internal carotid artery HR 0.5 (0.3–0.9)*
Anterior cerebral arteries (AcomA HR 1.7 (1.1–2.6)*
European, North American
and ACA combined) 8,382 (10,272) IIa
and Finnish
Posterior cerebral arteries (VA, BA HR 1.8 (1.2–2.8)*
and PCA combined)
Posterior communicating artery HR 2.0 (1.4–3.0)*
Geographical region91
Japanese population HR 2. 7 (1.8–4.1)* Japanese
8,382 (10,272) IIa
Finnish population HR 3.6 (2.1–6.5)* Finnish
*Multivariate analysis. ‡In the International Study of Unruptured Aneurysms, patients with unruptured aneurysms who had a family history of unruptured
aneurysms had an approximately 17-fold higher rupture rate (1.2% per year) than did those without such a family history (0.069% per year) matched for the
distribution of intracranial aneurysm size and location. §12‑fold higher risk of rupture in growing aneurysms, compared with nongrowing aneurysms, irrespective of
other features. ACA, anterior cerebral arteries (including pericallosal arteries); AComA, anterior communication artery; BA, basilar artery; IA, intracranial aneurysm;
NA, not applicable; PCA, posterior cerebral arteries; VA, vertebral arteries.

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a Geographical location b Aneurysm location

0.30 0.30
North American European ACA/Pcom/posterior
0.25 (other than Finnish) 0.25 ICA

Probability of rupture

Probability of rupture
Japanese MCA
0.20 0.20
Finnish
0.15 0.15

0.10 0.10

0.05 0.05

0 0
0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7
Years after diagnosis Years after diagnosis

c Hypertension d Earlier SAH

0.30 0.30
No hypertension No earlier SAH
0.25 Hypertension 0.25 Earlier SAH
Probability of rupture

Probability of rupture
0.20 0.20

0.15 0.15

0.10 0.10

0.05 0.05

0 0
0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7
Years after diagnosis Years after diagnosis

e Patient age f Aneurysm size

0.30 0.30
≥ 20 mm
<70 years
0.25 70+ years 0.25
Probability of rupture

Probability of rupture

0.20 0.20

0.15 0.15

0.10 0.10 10.0–19.9 mm

0.05 0.05 7.0–9.9 mm

<7 mm
0 0
0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7
Years after diagnosis Years after diagnosis

Figure 3 | Cumulative risk of rupture associated with different risk factors. Analysis of the PHASES
Nature data| set
Reviews Neurology
of 8,382 patients and 10,272 unruptured aneurysms has identified six factors that indepently contribute to the risk of
aneurysm rupture, including a | geographical location, b | aneurysm location, c | presence of hypertension, d | earlier
subarachnoid haemorrhage (SAH) from a different aneurysm, e | patient age and f | aneurysm size. Note that parts b–f
include patients from all geographical locations, including Japan and Finland. ACA, anterior cerebral arteries including
anterior communicating artery; ICA, internal carotid artery; MCA, middle cerebral artery; PCom, posterior communicating
artery; posterior, posterior cerebral arteries including vertebral and basilar artery.

Triggers of aneurysm rupture
Trigger factors for intracranial aneurysm rupture
include straining for defecation, use of caffeine, episodes
of anger, startling, sexual intercourse, nose-­blowing, and
vigorous physical exercise. The relative risks for these
trigger factors range from 2 for coffee intake to 20 for
startling94,105,106. The common denominator of these
triggers is that they induce a sudden and short increase
in blood pressure, which is interesting from a patho‑
physiological perspective. From a clinical perspective,
however, one cannot conclude that avoiding these activ‑
ities has any significant effect on the risk of rupture. For
example, patients with unruptured aneurysms would
need to avoid 1.3 million episodes of sexual intercourse
(that is 20,000 years of sexual activity) to avoid one
aneurysm rupture92.
Preventive unruptured aneurysm repair
For preventive aneurysm occlusion two modalities are
available: surgical clipping and endovascular coiling with
or without additional devices, such as regular stents or
flow-diverting stents. It must be noted that safety and
efficacy data from randomized controlled trials on rup‑
tured intracranial aneurysm repair cannot be extrap‑
olated to preventive interventions for UIAs. A direct
comparison between ruptured aneurysm and UIA repair

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Neck remnants
Residual filling of the neck,
or part of the neck, of an
aneurysm. Aneurysms that are
incompletely treated can
radiologically display a neck
remnant, which may need
observation and subsequent
treatment if the remnant is
enlarged.
would be inappropriate, because the morbidity and mor‑
tality risks are distinctly higher for ruptured aneurysm
repair than for UIA repair107,108.
Surgical aneurysm repair
According to a meta-analysis of 60 studies, which
included a total of 9,845 patients undergoing surgical
repair for 10,845 UIAs, the overall morbidity (includ‑
ing death) associated with surgical procedures was 6.7%
(99% CI 4.9–9.0), with a mortality of 1.7% (99% CI
0.9–3.0, I2 = 82%)109. However, the validity of these data
is limited, because the majority (85%) of the studies were
retrospective or single-centre studies without predefined
outcome measures or independent and blinded end point
analysis. Furthermore, only 32% of the studies included
in the meta-analysis reported aneurysm obliteration
rates. Obliteration rates were reported for 2,180 UIAs
(20.1%) and, of these UIAs, 91.8% (99% CI 90–93.2)
were completely occluded, 3.9% (99% CI 2.9–5.2) had
neck remnants, and 4.3% (99% CI 3.3–5.7) were incom‑
pletely occluded. Data on haemorrhage after surgical
repair of unruptured aneurysms were available in nine
publications and 7.9% of all patients. During the average
follow-up time of 1.2 years per patient, the haemorrhage
incidence was 0.38%. The main risk factors for unfavour‑
able outcome following surgical aneurysm repair were
posterior location of the aneurysm, increasing aneurysm
diameter (risk of rupture increased by approximately 1%
for each millimetre of growth), and age >55 years109.
Endovascular aneurysm repair
A meta-analysis published in 2010 is currently the most
comprehensive investigation on the safety of endo­vascular
repair of unruptured aneurysms110. The analysis included
5,044 patients from 71 studies, and a total of 5,771
UIAs. Data on 1,288 patients (25.5%) were derived from
high-quality studies, according to a classification based on
the Strengthening and Reporting of Observational Studies
in Epidemiology (STROBE) criteria. Treatment-related
unfavourable outcomes, including death, were reported
in 4.8% (99% CI 3.9–6.0) of patients. Early angiographic
results showed complete occlusion or neck remnant
occlusion, which were recorded as acceptable outcomes,
in 86.1% of unruptured aneurysms. Where recorded,
recurrences were detected in 24.4% of 1,316 aneurysm
patients during a follow‑up of 0.4–3.2 years. The annual
risk of haemor­rhage in patients undergoing endovascu‑
lar repair for an unruptured aneurysm was 0.2% (99% CI
0.1–0.3), but these data were limited to follow‑up periods
of ≤6 months in most (76.7%) of the patients.
A subsequent systematic review with an emphasis on
subgroups and precise methods of endovascular aneu‑
rysm repair, which included 97 studies and 7,172 patients
with unruptured aneurysms, reported that patient age
>52 years, aneurysm size >10 mm and location of UIAs
in the posterior circulation were the main risk factors for
poor outcome111. Endovascular UIA repair with ­liquid
embolic agents was also associated with an increased
risk of UIA rupture when compared with simple coiling.
Furthermore, among patients with unruptured aneurysms
who underwent treatment with additional endovascular
devices, unfavourable outcomes were reported in 7.1%
(99% CI 3.9–12.7) of patients with balloon-assisted
coiling, 9.3% (99% CI 4.9–16.9) of patients with stent-­
assisted coiling, and 11.5% (99% CI 4.9–24.6) of patients
with flow-diverting stents. It must be noted, however,
that the characteristics of unruptured aneurysms treated
with the additional endovascular devices differed from
those treated with coils only. For this reason, it is not clear
whether these increased risks of complications results
from the more-complex a­ neurysm characteristics, from
the devices, or both.
Ultimately, the choice of appropriate management
is complicated by a dearth of long-term follow-up data
with blinded end point adjudication, derived from pro‑
spective, multicentre, randomized cohorts of patients
with unruptured aneurysms (TABLE 4). The increasing
variety of endovascular devices, which includes flow-­
diverting stents and flow-disrupting devices, only
serves to compound the complicated choice of treatment
modality for UIAs.
More evidence is needed on the efficacy and long-
term complications of endovascular devices as, to date,
the only radiologically and clinically defined outcome
data derive from small, uncontrolled patient cohorts.
The lack of high-quality randomized controlled trials
investigating the efficacy of preventive unruptured cra‑
nial aneurysm treatments results in uncertainty and,
thus, high variability with regard to the best treatment
option within the clinical sphere. Owing to the length
of follow-up required for treatment efficacy studies, and
the small risk of rupture of intracranial aneurysms
and complications resulting from preventive treatments,
many randomized controlled trials on preventive aneu‑
rysm treatments are likely to remain uncompleted, as
was the fate of the Trial on Endovascular Aneurysm
Management (TEAM)112,113.
Assessment and management of UIAs
When counselling patients with UIAs on whether to have
preventive treatment, clinicians need to be clear on the
main goals of treatment (BOX 3). The aim is not only to
prevent SAH but also to find the strategy that yields the
highest number of quality-adjusted life years. Impaired
quality of life due to a complication from preventive UIA
treatment can be worse in terms of number of quality-­
adjusted life years than an SAH that occurs many years
after the decision not to occlude the aneurysm.
An argument often used in favour of preventive treat‑
ment is that it is an investment for the future. Clinicians
should realize, however, that with the exception of one
study from Finland, long-term follow-up data on the
risk of aneurysm rupture are lacking. Furthermore, it is
not possible to calculate the long-term risk of rupture
by simply multiplying the 5-year risk of rupture with
the estimated years of life remaining114. Such a calcula‑
tion ignores two key points: growth and rupture rates
are not constant over time64, and the risk of rupture of
aneurysms seems to decline over time. In the afore‑
mentioned mentioned long-term follow‑up study from
Finland, all ­ruptures occurred within the initial 25 years
of follow-up89,91.

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Preventive treatment can use the UIATS as a comprehensive guide to show

Clinicians who are highly specialized in UIA research
and treatment consider numerous factors before decid‑
ing on the appropriate management of a patient present‑
ing with an unruptured aneurysm. Factors affecting the
manage­ment choice include the life expectancy of the
patient, the estimated risk of rupture, the risk of com‑
plications of preventive treatment, and the level of anx‑
iety caused by the awareness of having an unruptured
aneurysm115,116. Most specialists agree on the overall
relevance of these factors, but the importance of indi‑
vidual factors is incompletely understood. Conflicting
opinions on which treatment factors deserve more
credence have resulted in uncertainties, and varia‑
tions in clinical practice remain, especially among less
informed clinicians9,115.
The absolute 5-year risk of rupture for intracranial
aneurysms can be estimated, but no robust calculation
is available to estimate the overall risk of preventive
treatment91. A risk score for preventive endovascular
­treatment is based on the size and location of the aneu‑
rysm, as well as the presence or absence of previous
cerebral ischaemic events117. Robust data are lacking
for estimation of the overall risk of preventive treat‑
ment. Current data or risk estimations are not derived
from prospective data aggregates and blinded outcome
assessments.
The Unruptured Intracranial Aneurysm Treatment
Scoring (UIATS) system was designed to help balance
the risk of rupture against the risk of complications
from preventive treatment118. The UIATS system was
derived from a consensus among 69 international and
multi­disciplinary aneurysm specialists. Clinicians not
specialized in the management of patients with UIAs
how a large group of specialists might manage an indi‑
vidual patient with UIAs. However, given the limitations
of the existing prediction models and scoring systems,
including PHASES and UIATS, the resulting estimates
are not decisive but, rather, serve as a starting point.
Clinicians must not overlook the fact that the patient
ultimately decides whether or not to receive preventive
treatment for a UIA. Therefore, clinicians must make
sure that each patient fully understands the actual risk
estimates — a process that can be time-consuming
and iterative. Finally, one must not forget that only the
patient can appreciate the levels of anxiety associated
with preventive treatment or having to live with an
unruptured aneurysm (BOX 3).
Conservative management
If the decision is made not to intervene endovascularly
or surgically, patients with UIAs are often advised to
undergo follow-up imaging to monitor UIA growth.
Enlarged aneurysms, which are defined by growth
>1 mm in any direction, have an increased risk of rup‑
ture. UIA growth can also suggests that an aneurysm
is — or at least has been — unstable. Deciding on the
frequency of f­ ollow-up imaging is difficult, however,
because aneurysm growth is discontinuous over time64.
Follow-up imaging within the first year of diagnosis
is considered unnecessary, as the percentage of aneu‑
rysms that grow during this time is low, as is the typ‑
ical extent of aneurysm growth88 (FIG. 2). In a recent
meta-­analysis of individual data from 1,507 patients
and a total of 1,909 unruptured aneurysms, the 3-year
growth risk ranged from <5% to >42%, and the 5-year
growth risk ranged from <9% to >60%, depending on

Table 4 | Prospective cohort studies on the risk of intracranial aneurysm rupture

Study Untreated cohort Number Annual risk (%) of Median follow‑up Number of Determinants for
(recruitment size (population) of UIAs rupture (95% CI in (range) in years SAHs during aneurysm rupture
years) brackets) follow‑up
ISUIA83 1,692 (European 2,686 0.95 (0.79–1.15) 9.0 (0–15) 59 IA size and location
(1991–1998) and North
American)
Juvela et al.89 142 (Finnish) 181 1.1 (NA) 21.0 (0–52) 34 Smoking, IA size and
(1956–1978) location, patient age
(inverse relationship)
SUAVe Study84 374 (Japanese) 448 0.54 (NA) 2.1 (0–7) 7 IA size and multiplicity,
(2000–2004) hypertension and
patient age
Ishibashi et al.86* 419 (Japanese) 529 1.4 3.2 (0–22)* 19 IA size and location,
(2003–2006) previous SAH from
other aneurysm
Wermer et al.88* 93 (European) 125 NA 2.2 (0–15)* 1 Previous SAH from
(2002–2004) other aneurysm,
familial IAs
UCAS87 5,720 (Japanese) 6,697 0.95 (0.79–1.15) 1.0 (0–9) 111 IA location and
(2001–2004) morphology
Murayama 2,252 (Japanese) 2,897 0.76 (0.58–0.98) NA 56 IA size, location and
et al.85 morphology, previous
(2003–2012) SAH from other IA
*These prospective cohort studies included a retrospective component, in case an aneurysm was already present before the start of follow‑up (Ishibashi et al. n = 17;
Wermer et al. n = 40). IA, intracranial aneurysm; UIA, unruptured intracranial aneurysm; NA, not applicable; SAH, subarachnoid haemorrhage.

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Box 3 | Dos and don’ts for the clinical management of aneurysms
Dos
• Remember that risk predictions and scoring systems are the beginning rather than
the end of the discussion with the patient, and are not definitive
• Provide patient counselling on the risk of and risk factors for aneurysm rupture,
and explain that the overall short term risk of rupture is small
• Advise smoking cessation
• Treat hypertension
• Refer the patient to a dedicated cerebrovascular centre
• Advise follow‑up imaging for conservatively managed patients with aneurysms
Don’ts
• Avoid emotive terms, such as ‘ticking time bomb’
• Avoid assessing aneurysms based on a single risk factor, such as diameter or location
• Do not impose lifestyle restrictions, such as on sexual activity, sports or flying
• Do not advise radiological screening of relatives for aneurysms unless the patient has
a history of two or more first-degree relatives with aneurysms or subarachnoid
haemorrhage
six risk factors: population, age, history of SAH, and
aneurysm location, size and shape (Backes, D. et al.
unpublished work).
To date, clinical trials have not provided data to sup‑
port medical treatment to reduce the risk of rupture.
Nevertheless, it seems logical to treat hypertension in
people with unruptured aneurysms, not only with the
purpose of reducing the risk of rupture, but also to
reduce the risk of cardiovascular disease in general119.
Patients should also be advised to quit smoking because,
as previously mentioned, smoking notably increases the
risk of aneurysm rupture89.
Conclusions
Existing data on the risk of intracranial aneurysm rup‑
ture is derived from numerous studies with different
levels of evidence. These data might not be general‑
izable to all unruptured aneurysms, because the ana‑
lysed cohorts all consisted of patients who, on the basis
of advice provided by their clinicians, decided not to
undergo preventive treatment. Thus, such studies have
a high selection bias with regard to factors such as
geographical location, age, previous medical history
and family history of the patient, and site and size of
the aneurysm.
The accuracy of studies investigating existing or
novel risk factors for intracranial aneurysm rup‑
ture must be improved. One approach that could be
adopted fairly swiftly to improve accuracy is to establish
common definitions. Implementation of such a strat‑
egy would allow data to be pooled easily. Researchers
and clinicians must also ensure that the technologies
used in studies generate reliable data. Most studies on
UIAs have relied on imaging methods that show the
lumen of the aneurysm rather than the aneurysm itself.
Furthermore, when new risk factors for UIA rupture
are identified, investigators should use cohort studies
for validation.
To gain a comprehensive understanding of the
determinants of UIA rupture risk, we need to investi‑
gate the physiological processes that are incompletely
understood. For example, small UIAs (<5 mm) typically
have a low risk of rupture but, for reasons that remain
unclear, some do rupture. Such events illustrate that the
risk of rupture cannot be determined solely by the size
or location of a UIA. Furthermore, the emerging role
of inflammation in UIA rupture could be investigated
further. To increase our understanding in this area,
researchers can utilize advanced imaging techniques
that are already used in clinical practice, along with
contrast enhancement MRI73. It is also imperative to
develop accurate models that predict the efficacy and
risk of complications of preventive treatment. Currently,
we only have rough estimates of complication rates, lim‑
ited knowledge of risk factors, and no robust prediction
models.
Novel imaging techniques, such as high-field mag‑
netic resonance tomography, can show the wall of the
aneurysm, and even distinct areas of structural insta‑
bility120. Together with histological and genetic studies
of the aneurysm wall, advanced imaging studies could
provide better insight into the pathways and processes
that lead to aneurysm development and rupture. Finally,
in view of the improved understanding of the path‑
ways of UIA rupture, new treatment avenues should
be explored for aneurysms that are not amenable to
preventive occlusion. A timely approach would be
to investigate the effects of hypertension treatment in
combination with a low-risk anti-inflammatory drug,
such as aspirin, on the risk of UIA rupture in patients
who do not undergo preventive aneurysm occlusion.

1. Vernooij, M. W. et al. Incidental findings on brain MRI
in the general population. N. Engl. J. Med. 357,
1821–1828 (2007).
2. Vlak, M. H., Algra, A., Brandenburg, R. & Rinkel, G. J.
Prevalence of unruptured intracranial aneurysms, with
emphasis on sex, age, comorbidity, country, and time
period: a systematic review and meta-analysis. Lancet.
Neurol. 10, 626–636 (2011).
3. Etminan, N. et al. Age of collagen in intracranial
saccular aneurysms. Stroke 45, 1757–1763 (2014).
4. Etminan, N. et al. Exploring the age of intracranial
aneurysms using carbon birth dating: preliminary
results. Stroke 44, 799–802 (2013).
5. Weir, B. Unruptured intracranial aneurysms: a review.
J. Neurosurgery 96, 3–42 (2002).
6. Gabriel, R. A. et al. Ten-year detection rate of brain
arteriovenous malformations in a large, multiethnic,
defined population. Stroke 41, 21–26 (2010).
7. Brown, R. D. Jr & Broderick, J. P. Unruptured
intracranial aneurysms: epidemiology, natural history,
management options, and familial screening. Lancet
Neurol. 13, 393–404 (2014).
8. Nieuwkamp, D. J. et al. Changes in case fatality of
aneurysmal subarachnoid haemorrhage over time,
according to age, sex, and region: a meta-analysis.
Lancet Neurol. 8, 635–642 (2009).
9. Krings, T. et al. Intracranial aneurysms: from vessel
wall pathology to therapeutic approach. Nat. Rev.
Neurol. 7, 547–559 (2011).
10. Krings, T., Geibprasert, S. & terBrugge, K. G.
Pathomechanisms and treatment of pediatric
aneurysms. Childs Nerv. Syst. 26, 1309–1318 (2010).
11. Darsaut, T. E. et al. Uncertainty and agreement in the
management of unruptured intracranial aneurysms.
J. Neurosurgery 120, 618–623 (2014).
12. Etminan, N. & Rinkel, G. J. Cerebral aneurysms:
Cerebral aneurysm guidelines — more guidance
needed. Nat. Rev. Neurol. 11, 490–491 (2015).
13. Thompson, B. G. et al. Guidelines for the management
of patients with unruptured intracranial aneurysms:
a guideline for healthcare professionals from the
american heart association/american stroke
association. Stroke 46, 2368–2400 (2015).
14. Kassam, A., Horowitz, M., Chang, Y. F. & Peters, D.
Altered arterial homeostasis and cerebral aneurysms:
a review of the literature and justification for a search
of molecular biomarkers. Neurosurgery 54,
1199–1211(2004).
15. Frosen, J. et al. Lipid accumulation, lipid oxidation,
and low plasma levels of acquired antibodies against
oxidized lipids associate with degeneration and
rupture of the intracranial aneurysm wall. Acta
Neuropathol. Commun. 1, 71 (2013).
16. Frosen, J. et al. Saccular intracranial aneurysm:
pathology and mechanisms. Acta Neuropathol. 123,
http://dx.doi.org/10.1007/s00401-011-0939-3
(2012).
17. Etminan, N. et al. Cerebral aneurysms: formation,
progression, and developmental chronology. Transl.
Stroke Res. 5, 167–173 (2014).

NATURE REVIEWS | NEUROLOGY ADVANCE ONLINE PUBLICATION | 13

©
2
0
1
6
M
a
c
m
i
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u
b
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i
s
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e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

18. Ronkainen, A. et al. Familial intracranial aneurysms.
Lancet 349, 380–384 (1997).
19. Bor, A. S. et al. Clinical, radiological, and flow-related
risk factors for growth of untreated, unruptured
intracranial aneurysms. Stroke 46, 42–48 (2015).
20. Brown, R. D. Jr et al. Screening for brain aneurysm in
the Familial Intracranial Aneurysm study: frequency
and predictors of lesion detection. J. Neurosurgery
108, http://dx.doi.org/10.3171/JNS/2008/
108/6/1132 (2008).
21. Beridze, N. & Frishman, W. H. Vascular Ehlers–Danlos
syndrome: pathophysiology, diagnosis, and prevention
and treatment of its complications. Cardiol. Rev. 20,
4–7 (2012).
22. Chan, Y. C. et al. Ten-year epidemiological review of
in‑hospital patients with Marfan syndrome. Ann. Vasc.
Surg. 22, 608–612 (2008).
23. van den Berg, J. S., Limburg, M. & Hennekam, R. C.
Is Marfan syndrome associated with symptomatic
intracranial aneurysms? Stroke 27, 10–12 (1996).
24. Juvela, S., Poussa, K. & Porras, M. Factors affecting
formation and growth of intracranial aneurysms. A long
term follow‑up study. Stroke 32, 485–491 (2001).
25. Vlak, M. H., Rinkel, G. J. E., Greebe, P. & Algra, A.
Independent risk factors for intracranial aneurysms
and their joint effect: a case–control study. Stroke 44,
984–987 (2013).
26. Ferns, S. P. et al. De novo aneurysm formation and
growth of untreated aneurysms: a 5‑year MRA
follow‑up in a large cohort of patients with coiled
aneurysms and review of the literature. Stroke 42,
313–318 (2010).
27. Wermer, M. J. et al. Follow‑up screening after
subarachnoid haemorrhage: frequency and
determinants of new aneurysms and enlargement of
existing aneurysms. Brain 128, 2421–2429 (2005).
28. Lindgren, A. E. et al. De novo aneurysm formation in
carriers of saccular intracranial aneurysm disease in
Eastern Finland. Stroke 47, http://dx.doi.org/10.1161/
STROKEAHA.115.012573 (2016).
29. Bor, A. S., Rinkel, G. J., van Norden, J. &
Wermer, M. J. Long-term, serial screening for
intracranial aneurysms in individuals with a family
history of aneurysmal subarachnoid haemorrhage:
a cohort study. Lancet Neurol. 13, 385–392 (2014).
30. Vlak, M. H., Rinkel, G. J. E., Greebe, P. & Algra, A.
Risk of rupture of an intracranial aneurysm based on
patient characteristics: a case–control study. Stroke
44, 1256–1259 (2013).
31. Alg, V. S., Sofat, R., Houlden, H. & Werring, D. J.
Genetic risk factors for intracranial aneurysms: a meta-
analysis in more than 116,000 individuals. Neurology
80, 2154–2165 (2013).
32. Ruigrok, Y. M. & Rinkel, G. J. E. Genetics of intracranial
aneurysms. Stroke. 39, 1049–1055 (2008).
33. Ruigrok, Y. M. et al. Association analysis of genes
involved in the maintenance of the integrity of the
extracellular matrix with intracranial aneurysms in a
Japanese cohort. Cerebrovasc. Dis. 28, 131–134
(2009).
34. Onda, H. et al. Genomewide-linkage and haplotype-
association studies map intracranial aneurysm to
chromosome 7q11. Am. J. Hum. Genet. 69, 804–819
(2001).
35. Fang, H. in Cerebrovascular Diseases (eds Wright, I. S.
& Millikan, C. H.) 17–22 (Grune and Stratton, 1958).
36. Lasheras, J. C. The biomechanics of arterial
aneurysms. Annu. Rev. Fluid Mech. 39, 293–319
(2007).
37. Frosen, J. Smooth muscle cells and the formation,
degeneration, and rupture of saccular intracranial
aneurysm wall — a review of current
pathophysiological knowledge. Transl. Stroke Res. 5,
347–356 (2014).
38. Steiger, H. J. Pathophysiology of development and
rupture of cerebral aneurysms. Acta Neurochir. Suppl.
(Wien) 48, 1–57 (1990).
39. Meng, H., Tutino, V. M., Xiang, J. & Siddiqui, A. High
WSS or low WSS? Complex interactions of
hemodynamics with intracranial aneurysm initiation,
growth, and rupture: toward a unifying hypothesis.
Am. J. Neuroradiol. 35, 1254–1262 (2014).
40. Bor, A. S., Velthuis, B. K., Majoie, C. B. & Rinkel, G. J.
Configuration of intracranial arteries and development
of aneurysms: a follow‑up study. Neurology 70,
700–705 (2008).
41. Castro, M. A., Putman, C. M., Sheridan, M. J. &
Cebral, J. R. Hemodynamic patterns of anterior
communicating artery aneurysms:a possible
association with rupture. Am. J. Neuroradiol. 30,
297–302 (2009).
42. Cebral, J. R. et al. Wall mechanical properties and
hemodynamics of unruptured intracranial aneurysms.
AJNR Am. J. Neuroradiol. 36, 1695–1703 (2015).
43. Cebral, J. R., Mut, F., Weir, J. & Putman, C.
Quantitative characterization of the hemodynamic
environment in ruptured and unruptured brain
aneurysms. Am. J. Neuroradiol. 32, 145–151
(2010).
44. Cebral, J. R., Mut, F., Weir, J. & Putman, C. M.
Association of hemodynamic characteristics and
cerebral aneurysm rupture. Am. J. Neuroradiol. 32,
264–272 (2010).
45. Wong, G. K. & Poon, W. S. Current status of
computational fluid dynamics for cerebral aneurysms:
the clinician’s perspective. J. Clin. Neurosci. 18,
1285–1288 (2011).
46. Alfano, J. M. et al. Intracranial aneurysms occur more
frequently at bifurcation sites that typically experience
higher hemodynamic stresses. Neurosurgery 73,
497–505 (2013).
47. Geers, A. J. et al. Patient-specific computational
hemodynamics of intracranial aneurysms from 3D
rotational angiography and CT angiography: an in vivo
reproducibility study. Am. J. Neuroradiol. 32,
581–586 (2010).
48. Jing, L. et al. Morphologic and hemodynamic analysis
in the patients with multiple intracranial aneurysms:
ruptured versus unruptured. PLoS ONE 10,
e0132494 (2015).
49. Meckel, S. et al. In vivo visualization and analysis of
3D hemodynamics in cerebral aneurysms with flow-
sensitized 4D MR imaging at 3 T. Neuroradiology 73,
473–484 (2008).
50. Schneiders, J. J. et al. Additional value of intra-
aneurysmal hemodynamics in discriminating ruptured
versus unruptured intracranial aneurysms. Am.
J. Neuroradiol. 36, 1920–1926 (2015).
51. Takao, H. et al. Hemodynamic differences between
unruptured and ruptured intracranial aneurysms
during observation. Stroke 43, 1436–1439 (2012).
52. Kilic, T. et al. Expression of structural proteins and
angiogenic factors in normal arterial and unruptured
and ruptured aneurysm walls. Neurosurgery 57,
997–1007 (2005).
53. Kurki, M. I. et al. Upregulated signaling pathways in
ruptured human saccular intracranial aneurysm wall:
an emerging regulative role of Toll-like receptor
signaling and nuclear factor‑κB, hypoxia-inducible
factor-1A, and ETS transcription factors. Neurosurgery
68, 1667–1675 (2011).
54. Starke, R. M. et al. The role of oxidative stress in
cerebral aneurysm formation and rupture. Curr.
Neurovasc Res. 10, 247–255 (2013).
55. Sluijter, J. P., Smeets, M. B., Velema, E.,
Pasterkamp, G. & de Kleijn, D. P. Increased collagen
turnover is only partly associated with collagen fiber
deposition in the arterial response to injury.
Cardiovasc. Res. 61, 186–195 (2004).
56. Rowe, A. J., Finlay, H. M. & Canham, P. B. Collagen
biomechanics in cerebral arteries and bifurcations
assessed by polarizing microscopy. J. Vasc. Res. 40,
406–415 (2003).
57. Austin, G., Fisher, S., Dickson, D., Anderson, D. &
Richardson, S. The significance of the extracellular
matrix in intracranial aneurysms. Ann. Clin. Lab. Sci.
23, 97–105 (1993).
58. Chalouhi, N., Hoh, B. L. & Hasan, D. Review of
cerebral aneurysm formation, growth, and rupture.
Stroke 44, 3613–3622 (2013).
59. Backes, D. et al. PHASES score for prediction of
intracranial aneurysm growth. Stroke 46, 1221–1226
(2015).
60. Chien, A. et al. Enlargement of small, asymptomatic,
unruptured intracranial aneurysms in patients with no
history of subarachnoid hemorrhage: the different
factors related to the growth of single and multiple
aneurysms. J. Neurosurgery 119, 190–197 (2013).
61. Villablanca, J. P. et al. Natural history of asymptomatic
unruptured cerebral aneurysms evaluated at ct
angiography: growth and rupture incidence and
correlation with epidemiologic risk factors. Radiology
269, 258–265 (2013).
62. Chang, H. S. Simulation of the natural history of
cerebral aneurysms based on data from the
International Study of Unruptured Intracranial
Aneurysms. J. Neurosurg. 104, 188–194 (2006).
63. Chatziprodromou, I., Poulikakos, D. & Ventikos, Y. On
the influence of variation in haemodynamic conditions
on the generation and growth of cerebral aneurysms
and atherogenesis: a computational model.
J. Biomechan. 40, 3626–3640 (2007).
64. Koffijberg, H., Buskens, E., Algra, A., Wermer, M. J. &
Rinkel, G. J. E. Growth rates of intracranial aneurysms:
exploring constancy. J. Neurosurg. 109, 176–185
(2008).
65. Ha, S. K., Lim, D. J., Kim, S. D. & Kim, S. H. Rupture
of de novo anterior communicating artery aneurysm
8 days after the clipping of ruptured middle cerebral
artery aneurysm. J. Kor. Neurosurg. Soc. 54,
236–238 (2013).
66. Schebesch, K. M., Doenitz, C., Zoephel, R.,
Finkenzeller, T. & Brawanski, A. T. Recurrent
subarachnoid hemorrhage caused by a de novo basilar
tip aneurysm developing within 8 weeks after clipping
of a ruptured anterior communicating artery aneurysm:
case report. Neurosurgery 62, E259–E260 (2008).
67. Yasuhara, T., Tamiya, T., Sugiu, K., Inoue, S. &
Ohmoto, T. De novo formation and rupture of an
aneurysm. Case report. J. Neurosurg. 97, 697–700
(2002).
68. Okazaki, T. et al. De novo formation and rupture of an
intracranial aneurysm 10 months after normal
findings on conventional magnetic resonance
angiography in a patient with no history of
intracranial lesions: case report. Neurol. Med. Chir.
50, 309–312 (2010).
69. Sim, J. H., Kim, S. C. & Kim, M. S. Early development
and rupture of de novo aneurysm — case report.
Neurol. Med. Chir. 42, 334–337 (2002).
70. Backes, D., Rinkel, G. J., Laban, K. G., Algra, A.
& Vergouwen, M. D. Patient- and aneurysm-specific
risk factors for intracranial aneurysm growth:
systematic review and meta-analysis. Stroke 47,
http://dx.doi.org/10.1161/STROKEAHA.115.012162
(2016).
71. Hasan, D. et al. Early change in ferumoxytol-enhanced
magnetic resonance imaging signal suggests unstable
human cerebral aneurysm: a pilot study. Stroke 43,
3258–3265 (2012).
72. Hasan, D. M. et al. Aspirin as a promising agent for
decreasing incidence of cerebral aneurysm rupture.
Stroke 42, 3156–3162 (2011).
The first study to highlight the protective effect
of aspirin on aneurysm rupture in humans.
73. Edjlali, M. et al. Does aneurysmal wall enhancement
on vessel wall-MRI help to distinguish stable from
unstable intracranial aneurysms? Stroke 45,
3704–3706 (2014).
74. Hasan, D. M. et al. Evidence that acetylsalicylic acid
attenuates inflammation in the walls of human
cerebral aneurysms: preliminary results. J. Am. Heart
Assoc. 2, e000019 (2013).
75. Hasan, D. M. et al. Imaging aspirin effect on
macrophages in the wall of human cerebral
aneurysms using ferumoxytol-enhanced MRI:
preliminary results. J. Neuroradiol. 40, 187–191
(2013).
76. Chalouhi, N. et al. Biology of intracranial aneurysms:
role of inflammation. J. Cereb. Blood Flow Metab. 32,
1659–1676 (2012).
77. Chalouhi, N., Jabbour, P. & Hasan, D. Inflammation,
macrophages, and targeted imaging in intracranial
aneurysms. World Neurosurg. 81, 206–208 (2014).
78. Starke, R. M. et al. Vascular smooth muscle cells in
cerebral aneurysm pathogenesis. Transl. Stroke Res.
5, 338–346 (2014).
79. Starke, R. M. et al. Tumor necrosis factor-α modulates
cerebral aneurysm formation and rupture. Transl.
Stroke Res. 5, 269–277 (2014).
80. Kleinloog, R. et al. RNA sequencing analysis of
intracranial aneurysm walls reveals involvement of
lysosomes and immunoglobulins in rupture. Stroke
47, 1286–1293 (2016).
81. Aoki, T. et al. PGE2-EP2 signalling in endothelium is
activated by haemodynamic stress and induces
cerebral aneurysm through an amplifying loop via
NF‑κB. Br. J. Pharmacol. 163, 1237–1249 (2011).
82. Hasan, D. et al. Upregulation of cyclooxygenase‑2
(COX‑2) and microsomal prostaglandin E2 synthase‑1
(mPGES‑1) in wall of ruptured human cerebral
aneurysms: preliminary results. Stroke 43,
1964–1967 (2012).
83. Wiebers, D. O. et al. Unruptured intracranial
aneurysms: natural history, clinical outcome, and risks
of surgical and endovascular treatment. Lancet 362,
103–110 (2003).
The largest cohort study on unruptured rupture
risk in a white population to date.
84. Sonobe, M., Yamazaki, T., Yonekura, M. & Kikuchi, H.
Small unruptured intracranial aneurysm verification
study. SUAVe study, Japan. Stroke 41, 1969–1977
(2010).

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©
2
0
1
6
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a
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m
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i
s
h
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r
s
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i
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i
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,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
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a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 REVIEWS

85. Murayama, Y. et al. Risk analysis of unruptured
intracranial aneurysms: prospective 10‑year cohort
study. Stroke 47, 365–371 (2016).
86. Ishibashi, T. et al. Unruptured intracranial aneurysms:
incidence of rupture and risk factors. Stroke 40,
313–316 (2009).
87. Morita, A. et al. The natural course of unruptured
cerebral aneurysms in a Japanese cohort. N. Engl.
J. Med. 366, 2474–2482 (2012).
Currently, the largest cohort study on aneurysm
rupture risk in a Japanese population.
88. Wermer, M. J. et al. Yield of short-term follow‑up CT/
MR angiography for small aneurysms detected at
screening. Stroke 37, 414–418 (2006).
89. Juvela, S., Poussa, K., Lehto, H. & Porras, M.
Natural history of unruptured intracranial
aneurysms: a long-term follow‑up study. Stroke 44,
2414–2421 (2013).
90. Friedman, J. A. et al. Small cerebral aneurysms
presenting with symptoms other than rupture.
Neurology 57, 1212–1216 (2001).
91. Greving, J. P. et al. Development of the PHASES score
for prediction of risk of rupture of intracranial
aneurysms: a pooled analysis of six prospective cohort
studies. Lancet Neurol. 13, 59–66 (2014).
The largest pooled analysis of cohort studies on
aneurysm rupture risk to date.
92. Macleod, M. R. & White, P. M. Not tonight, darling,
I might get a headache. Stroke 42, 1807–1808
(2011).
93. Hasan, D. M., Hindman, B. J. & Todd, M. M. Pressure
changes within the sac of human cerebral aneurysms
in response to artificially induced transient increases
in systemic blood pressure. Hypertension 66,
324–331 (2015).
94. Vlak, M. H., Rinkel, G. J. E., Greebe, P., van der
Bom, J. G. & Algra, A. Trigger factors and their
attributable risk for rupture of intracranial aneurysms:
a case-crossover study. Stroke 42, 1878–1882
(2011).
95. Backes, D. et al. Increased incidence of subarachnoid
hemorrhage during cold temperatures and influenza
epidemics. J. Neurosurg. 125, 737–745 (2016).
96. Korja, M., Lehto, H. & Juvela, S. Lifelong rupture risk
of intracranial aneurysms depends on risk factors:
a prospective Finnish cohort study. Stroke 45,
1958–1963 (2014).
The only study on the lifetime risk of aneurysm
rupture derived from a Finnish cohort.
97. Feigin, V. L. et al. Smoking and elevated blood
pressure are the most important risk factors for
subarachnoid hemorrhage in the Asia–Pacific region.
An overview of 26 cohorts involving 306,620
participants. Stroke 36, 1360–1365 (2005).
98. Broderick, J. P. et al. Greater rupture risk for familial
as compared to sporadic unruptured intracranial
aneurysms. Stroke 40, 1952–1957 (2009).
99. Backes, D. et al. Difference in aneurysm characteristics
between ruptured and unruptured aneurysms in
patients with multiple intracranial aneurysms. Stroke
45, 1299–1303 (2014).
100. Lindgren, A. E. et al. Irregular shape of intracranial
aneurysm indicates rupture risk irrespective of size in
a population-based cohort. Stroke http://dx.doi.
org/10.1161/STROKEAHA.115.012404 (2016).
101. Ujiie, H. et al. Effects of size and shape (aspect ratio)
on the hemodynamics of saccular aneurysms: a
possible index for surgical treatment of intracranial
aneurysms. Neurosurgery 45, 119–129 (1999).
102. Rahman, M. et al. Size ratio correlates with
intracranial aneurysm rupture status: a prospective
study. Stroke 41, 916–920 (2010).
103. Kashiwazaki, D., Kuroda, S. & Sapporo, S. A. H. S. G.
Size ratio can highly predict rupture risk in intracranial
small (<5 mm) aneurysms. Stroke 44, 2169–2173
(2013).
104. de Rooij, N. K., Velthuis, B. K., Algra, A. &
Rinkel, G. J. E. Configuration of the circle of Willis,
direction of flow, and shape of the aneurysm as risk
factors for rupture of intracranial aneurysms.
J. Neurol. 256, 45–50 (2009).
105. Anderson, C. et al. Triggers of subarachnoid
hemorrhage. Role of physical exertion, smoking, and
alcohol in the Australasian Cooperative Research on
Subarachnoid Hemorrhage Study (ACROSS). Stroke
34, 1771–1776 (2003).
106. Fann, J. R., Kukull, W. A., Katon, W. J. &
Longstreth, W. T. Jr. Physical activity and subarachnoid
haemorrhage: a population based case–control study.
J. Neurol. Neurosurg. Psychiatry 69, 768–772 (2000).
107. McDougall, C. G. et al. The Barrow Ruptured
Aneurysm Trial. J. Neurosurg. 69, 135–144 (2011).
108. Molyneux, A. J. et al. International Subarachnoid
Aneurysm Trial (ISAT) of neurosurgical clipping versus
endovascular coiling in 2143 patients with ruptured
intracranial aneurysms: a randomised trial. Lancet
360, 1267–1274 (2002).
109. Kotowski, M. et al. Safety and occlusion rates of
surgical treatment of unruptured intracranial
aneurysms: a systematic review and meta-analysis
of the literature from 1990 to 2011. J. Neurol.
Neurosurg. Psychiatry 84, 42–48 (2013).
A comprehensive meta-analysis of the risks
associated with surgical treatment in patients
with unruptured intracranial aneurysms.
110. Naggara, O. N. et al. Endovascular treatment of
intracranial unruptured aneurysms: systematic review
and meta-analysis of the literature on safety and
efficacy. Radiology 256, 887–897 (2010).
111. Naggara, O. N. et al. Endovascular treatment of
intracranial unruptured aneurysms: a systematic
review of the literature on safety with emphasis on
subgroup analyses. Radiology 263, 828–835
(2012).
References 110 and 111 are comprehensive
meta-analyses of the risks associated with
endovascular treatment in patients with
unruptured intracranial aneurysms.
112. Raymond, J., Darsaut, T. E. & Molyneux, A. J. and
TEAM Collaborative Group A trial on unruptured
intracranial aneurysms (the TEAM trial): results,
lessons from a failure and the necessity for clinical care
trials. Trials 12, 64 (2011).
113. Raymond, J. et al. The TEAM trial: safety and efficacy
of endovascular treatment of unruptured intracranial
aneurysms in the prevention of aneurysmal
hemorrhages: a randomized comparison with
indefinite deferral of treatment in 2002 patients
followed for 10 years. Trials 9, 43 (2008).
114. Korja, M. & Kaprio, J. Controversies in epidemiology
of intracranial aneurysms and SAH. Nat. Rev. Neurol.
12, 50–55 (2016).
115. Etminan, N. et al. Multidisciplinary consensus on
assessment of unruptured intracranial aneurysms:
proposal of an international research group. Stroke
45, 1523–1530 (2014).
116. Greving, J. P., Rinkel, G. J. E., Buskens, E. & Algra, A.
Cost-effectiveness of preventive treatment of
intracranial aneurysms. New data and uncertainties.
Neurology. 73, 258–265 (2009).
117. Ji, W. et al. Risk Score for Neurological
Complications After Endovascular Treatment of
Unruptured Intracranial Aneurysms. Stroke 47,
971–978 (2016).
118. Etminan, N. et al. The unruptured intracranial
aneurysm treatment score: a multidisciplinary
consensus. Neurology 85, 881–889 (2015).
The first multidisciplinary consensus study of a
quantative scoring strategy for assessment of
patients with unruptured aneurysms.
119. US National Library of Medicine. ClinicalTrials.gov
https://clinicaltrials.gov/ct2/show/ NCT01206062
(2016).
120. Kleinloog, R. et al. Visualization of the Aneurysm Wall:
A 7.0 Tesla MRI Study. Neurosurgery 75, 614–622
(2014).
121. Tulamo, R. et al. Complement system becomes
activated by the classical pathway in intracranial
aneurysm walls. Lab Invest. 47, 168–179 (2009).
122. Frosen, J. et al. Remodeling of Saccular Cerebral
Artery Aneurysm Wall Is Associated With Rupture.
Histological Analysis of 24 Unruptured and 42
Ruptured Cases. Stroke 35, 2287–2293 (2004).
Acknowledgements
N.E. and G.J.R would like to thank S. Gingerich for the art-
work used in BOXES 1 and 2 and FIG. 1, and J. Greving for
creating FIG. 2 on the basis of data from the PHASES study.
Author contributions
N.E. and G.J.R. wrote the article. Both authors contributed
equally to the preparation of the manuscript, and drafted the
figures with S. Gingerich and J. Greving.
Competing interests
The authors declare no competing interests.

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