REVIEW ARTICLE
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C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
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CONTINUUM (MINNEAP MINN)
2 0 2 0 ; 26(2, CEREBROVASCULAR
DISEASE):478–498.
Address correspondence to
Dr Ynte Ruigrok, Department of
Neurology and Neurosurgery,
UMC Utrecht Brain Center,
University Medical Center
Utrecht, PO Box 85500, 3508 GA
Utrecht, the Netherlands,
ij.m.ruigrok@umcutrecht.nl.
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© 2020 American Academy
of Neurology.
478
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Management of
Unruptured Cerebral
Aneurysms and
Arteriovenous
Malformations
By Ynte M. Ruigrok, MD, PhD
ABSTRACT
PURPOSE OF REVIEW: Unruptured intracranial aneurysms and brain
arteriovenous malformations (AVMs) may be detected as incidental
findings on cranial imaging. This article provides a practical approach to
the management of unruptured intracranial aneurysms and unruptured
brain AVMs and reviews the risk of rupture, risk factors for rupture,
preventive treatment options with their associated risks, and the
approach of treatment versus observation for both types of vascular
malformations.
RECENT FINDINGS: For unruptured intracranial aneurysms, scoring systems on
the risk of rupture can help with choosing preventive treatment or
observation with follow-up imaging. Although the literature provides
detailed information on the complication risks of preventive treatment of
unruptured intracranial aneurysms, individualized predictions of these
procedural complication risks are not yet available. With observation with
imaging, growth of unruptured intracranial aneurysms can be monitored,
and prediction scores for growth can help determine the optimal timing of
monitoring. The past years have revealed more about the risk of
complications of the different treatment modalities for brain AVMs. A
randomized clinical trial and prospective follow-up data have shown that
preventive interventional therapy in patients with brain AVMs is associated
with a higher rate of neurologic morbidity and mortality compared with
observation.
SUMMARY: The risk of hemorrhage from both unruptured intracranial
aneurysms and brain AVMs varies depending on the number of risk factors
associated with hemorrhage. For both types of vascular malformations,
different preventive treatment options are available, and all carry risks
of complications. For unruptured intracranial aneurysms, the consideration
of preventive treatment versus observation is complex, and several
factors should be included in the decision making. Overall, it is
recommended that patients with unruptured asymptomatic brain AVMs
should be observed.
APRIL 2020
INTRODUCTION

V
ascular malformations are detected more frequently as incidental
findings on cranial imaging because of the higher frequency and
increased quality of imaging.1,2 This article focuses on two vascular
malformations: unruptured intracranial aneurysms and brain
arteriovenous malformations (AVMs).
Unruptured intracranial aneurysms are pathologic dilations at major branching
brain arteries (FIGURE 12-1A), which are found in approximately 3% of the adult
population.3,4 However, this prevalence may be underestimated; a recent
Japanese study showed the prevalence of unruptured intracranial aneurysms was
4.3% in 4070 persons undergoing imaging of the circle of Willis.5 Unruptured
intracranial aneurysms most often develop between the fourth and sixth decade
and are more prevalent in women than in men.3 Approximately 20% to 30% of
patients with unruptured aneurysms have more than one aneurysm.6
A brain AVM is characterized by a direct connection between arteries and
veins without a capillary bed in between. The connecting vessels consist of a
tangle of abnormal dilated vessels, and this tangle is called the nidus. Blood is
shunted from artery to vein through the nidus, which causes blood flow that is
higher than normal in both arteries and veins (FIGURE 12-1B).7 The prevalence of
brain AVMs is lower than that of unruptured intracranial aneurysms, although
reliable prevalence rates for brain AVMs in the literature are scarce.8 In a brain
MRI study in healthy volunteers, a brain AVM was detected in approximately 1 in
every 2000 brain MRI scans, translating to an estimated prevalence of 0.05%.9

FIGURE 12-1
Vascular malformations. Unruptured intracranial aneurysms (A) and brain arteriovenous
malformations (B).
Panel A reprinted with permission from medicalartstudio.com/efolio/aneurysm.html.4 Panel B reprinted
with permission from medicalartstudio.com/efolio/arteriovenous.html.7 © 2009 Medical Art Studio.

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UNRUPTURED CEREBRAL ANEURYSMS AND ARTERIOVENOUS MALFORMATIONS

Incidental brain AVMs are most commonly found in young adults between the
ages of 20 and 40 years and seem to be equally prevalent in men and women.10
They generally occur as single lesions, but up to 9% are multiple.11
Detection of an unruptured intracranial aneurysm or unruptured brain AVM
necessitates a decision on whether to preventively treat the lesion to prevent
hemorrhage in the future. Management is aimed at determining the risk of future
hemorrhage compared with the risk of intervention. This article provides a
practical approach to the management of unruptured intracranial aneurysms and
unruptured brain AVMs and reviews the risk of rupture, risk factors for rupture,

TABLE 12-1A Risk Factors for Aneurysm Rupture According to the PHASES Rupture
Risk Scorea

Risk Factor for Aneurysm Rupture Points

Population

North American, European (other than Finnish) 0

Japanese 3

Finnish 6

Hypertension

No 0

Yes 1

Age

Younger than 70 years 0

70 years or older 1

Size of aneurysm

<7.0 mm 0

7.0–9.9 mm 3

10.0–19.9 mm 6

≥20 mm 10

Earlier subarachnoid hemorrhage from another aneurysm

Yes 0

No 1

Site of aneurysm

Internal carotid artery 0

Middle cerebral artery 2

Anterior cerebral artery, posterior communicating artery, and posterior circulation 4

PHASES = Population, Hypertension, Age, Size of aneurysm, Earlier subarachnoid hemorrhage from another
aneurysm, and Site of aneurysm.
a
Modified with permission from Greving JP, et al, Lancet Neurol.14 © 2014 Elsevier.

480 APRIL 2020

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preventive treatment options with their associated risks, and the approach to
treatment versus observation for both types of vascular malformations.

UNRUPTURED INTRACRANIAL ANEURYSMS

The following paragraphs address the risk of rupture of unruptured intracranial
aneurysms, risk factors for rupture, preventive treatment options with their
associated risks, and the approach of treatment versus observation.

Risk of Rupture and Risk Factors for Rupture

Rupture of an aneurysm leads to a subarachnoid hemorrhage (SAH), which has a
major impact due to its devastating effects; one-third of patients die, and
one-third are rendered dependent.12 SAH is relatively rare with an incidence of 6
per 100,000 persons per year, and its incidence is declining.13 The relatively low
incidence of SAH indicates that many unruptured intracranial aneurysms will
never rupture. It is, therefore, important to understand the risk of rupture and
the risk factors for rupture to identify which unruptured intracranial aneurysms
are at high risk of rupturing.
In a meta-analysis of six prospective cohort studies on the risk of aneurysm
rupture, which included data from 8382 patients and a total of 10,272 unruptured
intracranial aneurysms, six independent risk factors for aneurysm rupture were
identified (TABLES 12-1A and 12-1B).14 Patient-related risk factors are patient age
of 70 years or older, a history of hypertension, previous SAH from another
aneurysm, and the patient's geographic region with patients in Finland and Japan
having an increased rupture risk. Aneurysm-related risk factors are the size and

Predicted 5-Year Risk of Rupture According to the PHASES Rupture TABLE 12-1B
Risk Scorea

Predicted 5-Year Risk of Rupture Score % Hazard Ratio (95% Confidence Interval)

≤2 0.4 (0.1–1.5)

3 0.7 (0.2–1.5)

4 0.9 (0.3–2.0)

5 1.3 (0.8–2.4)

6 1.7 (1.1–2.7)

7 2.4 (1.6–3.3)

8 3.2 (2.3–4.4)

9 4.3 (2.9–6.1)

10 5.3 (3.5–8.0)

11 7.2 (5.0–10.2)

≥12 17.8 (15.2–20.7)

PHASES = Population, Hypertension, Age, Size of aneurysm, Earlier subarachnoid hemorrhage from another
aneurysm, and Site of aneurysm.
a
Modified with permission from Greving JP, et al, Lancet Neurol.14 © 2014 Elsevier.

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UNRUPTURED CEREBRAL ANEURYSMS AND ARTERIOVENOUS MALFORMATIONS

site of the aneurysm with larger aneurysms and aneurysms located at the middle
cerebral artery and posterior circulation having an increased rupture risk.14
Based on these six key risk factors, a simple score for prediction of aneurysm
rupture risk, called the PHASES (Population, Hypertension, Age, Size of
aneurysm, Earlier subarachnoid hemorrhage from another aneurysm, and Site of
aneurysm) score, was developed, which provides absolute estimates for the
5-year risk of aneurysm rupture. This 5-year risk ranged from 0.25% in
individuals younger than 70 years without vascular risk factors with a
small-sized (<7 mm) internal carotid artery aneurysm to more than 15% in
patients aged 70 years or older with hypertension, a history of SAH, and a
giant-sized (>20 mm) posterior circulation aneurysm (TABLES 12-1A and 12-1B).
Some established risk factors that contribute to the rupture of aneurysms were
not included in the PHASES score. Sex, presence of multiple aneurysms, and
smoking are known risk factors and were evaluated as such; however, these
factors had no added value in predicting aneurysm rupture when the other six
risk factors were accounted for. Other risk factors, such as aneurysm size and
indices (including aspect ratio [ie, the ratio of aneurysm neck-to-dome length
to aneurysm neck width] and height to width ratio), were not recorded or
homogeneously defined within the different cohort studies and, therefore, could
not be included in the model. For these excluded patient-related and aneurysm-
related risk factors, only relative—not absolute—effects can be established.

PATIENT-RELATED RISK FACTORS IN ADDITION TO THE PHASES SCORE. Smoking

is the most important patient-related risk factor not included in the PHASES
prediction score. Five of the six cohort studies had data for smoking only at the
time of aneurysm detection and not for smoking status during follow-up. Only
one cohort study had data on smoking status during follow-up after aneurysm
detection.15 In this Finnish cohort study, current smokers were 3 times more
likely to have an aneurysm rupture than patients who had never smoked or who
had stopped smoking.15 Moreover, a meta-analysis on 26 longitudinal and
case-control studies on risk factors for SAH showed that smoking is an
independent risk factor for SAH.16
A positive family history of intracranial aneurysms has also been suggested as
a risk factor for aneurysm rupture. One study found a 17-times increased rupture
rate for familial compared with sporadic unruptured intracranial aneurysms.17
However, in this study, patients with familial and sporadic unruptured
intracranial aneurysms were recruited from different study populations
(patients with familial aneurysms from the Familial Intracranial Aneurysm
Study17 and patients with sporadic aneurysms from the International Study of
Unruptured Intracranial Aneurysms18), and the patients with familial
unruptured intracranial aneurysms were selected because they all smoked or had
hypertension or both, and both patients with familial and sporadic unruptured
intracranial aneurysms had aneurysms sized 7 mm or smaller.17 A recent study of
62 patients with 91 familial unruptured intracranial aneurysms and 412 patients
with 542 sporadic unruptured intracranial aneurysms from the same institution
suggested only a slightly, not statistically significant, increased risk of aneurysm
rupture for familial compared with sporadic unruptured intracranial aneurysms
(hazard ratio, 2.9; 95% confidence interval [CI], 0.6 to 14).19 Further studies
are needed to draw definite conclusions about the risk of rupture for familial
compared with sporadic unruptured intracranial aneurysms.

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ANEURYSM-RELATED RISK FACTORS IN KEY POINTS
ADDITION TO THE PHASES SCORE.
Aneurysm characteristics, including ● Rupture of an aneurysm
leads to a subarachnoid
aneurysm shape or morphology, and the hemorrhage, which has
direction of blood flow into the aneurysm devastating effects;
could not be included in the PHASES one-third of patients die,
prediction score because they were not and one-third are rendered
dependent.
recorded in most studies analyzed in the
14
PHASES study. A meta-analysis of risk ● The PHASES (Population,
factors for aneurysmal rupture found Hypertension, Age, Size of
strong evidence for irregular shape aneurysm, Earlier
subarachnoid hemorrhage
(including blebs and daughter sacs) as a
from another aneurysm, and
risk factor based on four prospective Site of aneurysm) score
cohort studies with a pooled odds ratio of provides absolute estimates
20
4.8 (95% CI, 2.7 to 8.7). Aneurysm for the 5-year risk of rupture
indices, including aspect ratio (the ratio of of unruptured intracranial
aneurysms based on the
aneurysm neck-to-dome length to presence of these different
aneurysm neck width) and height to risk factors.
width ratio, were also found to be
associated with a high risk of rupture, ● Depending on the number
of different risk factors
but these factors should first be present, the 5-year risk of
confirmed in adequately powered rupture of unruptured
prospective studies that include intracranial aneurysms
20 ranges from 0.25% to more
multivariable analyses.
FIGURE 12-2 than 15%.
Treatment modalities to preventively
Preventive Treatment treat unruptured intracranial aneurysms ● Patient-related risk
To occlude the aneurysm, two different (A): surgical clipping (B) and endovascular factors for rupture of
preventive treatment modalities are coiling (C). unruptured intracranial
Reprinted from mayfieldclinic.com/ aneurysms in addition to the
available: surgical clipping and endovascular PHASES score are smoking
pe-aneurun.htm.21 © 2018 Mayfield Clinic.
coiling (FIGURE 12-2).21 Endovascular and, possibly, a positive
coiling can be executed with or without family history of intracranial
additional devices, such as regular stents or flow-diverting stents. Preventive aneurysms.
treatment of unruptured intracranial aneurysms has improved over time.22
● In addition to the PHASES
Different systematic reviews and meta-analyses have assessed the complication score, aneurysm-related
rates and case-fatality risk of the two different preventive treatment options.23–27 risk factors for unruptured
The results for surgical clipping and endovascular treatment should not be intracranial aneurysm
rupture are irregular shape
compared because the included studies were not randomized clinical trials,
and possibly aspect ratio
which may have led to various sources of bias, such as selection bias. So far, only (the ratio of aneurysm
one randomized clinical trial has been performed comparing surgical clipping neck-to-dome length to
and endovascular treatment, in 260 patients with unruptured intracranial aneurysm neck width) and
aneurysms, and no differences were shown in permanent morbidity at 1 year.28 height to width ratio.

● Unruptured intracranial
SURGICAL CLIPPING. In a systematic review and meta-analysis on complication aneurysms can be
rates and case fatality risk of endovascular and neurosurgical treatment of preventively treated by
unruptured intracranial aneurysms, 114 studies including 106,433 patients with surgical clipping or
endovascular coiling. Both
108,263 unruptured intracranial aneurysms were analyzed, making it the largest treatments have a risk of
overview of treatment outcomes for these aneurysms.25 For the outcome of complications, and different
neurosurgical treatment using clipping, 54 studies were analyzed; the pooled factors associated with an
complication risk was 8.34% (95% CI, 6.25% to 11.10%), and the case fatality rate increased risk have been
identified.
was 0.10% (95% CI, 0.00% to 0.20%). The complication risks as established in

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UNRUPTURED CEREBRAL ANEURYSMS AND ARTERIOVENOUS MALFORMATIONS

that review were slightly higher than those established in previous reviews,23,24
which may be explained by the use of more liberal inclusion criteria in the
more recent review.25 Several factors associated with neurosurgical treatment
complications were identified: age (odds ratio per year increase, 1.02; 95% CI,
1.01 to 1.02), male sex (odds ratio, 2.33; 95% CI, 1.18 to 3.13), coagulopathy
(odds ratio, 2.14; 95% CI, 1.13 to 4.06), use of anticoagulants (odds ratio, 6.36;
95% CI, 2.55 to 15.85), smoking (odds ratio, 1.95; 95% CI, 1.36 to 2.79), hypertension
(odds ratio, 1.45; 95% CI, 1.03 to 2.03), diabetes mellitus (odds ratio, 2.38; 95% CI,
1.54 to 3.67), congestive heart failure (odds ratio, 2.71; 95% CI, 1.57 to 4.69),
posterior aneurysm location (odds ratio, 7.25; 95% CI, 3.70 to 14.20), and
aneurysm calcification (odds ratio, 2.89; 95% CI, 1.35 to 6.18).25 The complication
risks decreased through the years with more recent studies reporting lower
risks.25 Only a minority of studies reported on aneurysm obliteration rates. In an
earlier review on neurosurgical clipping complications, 32% had data on
aneurysm obliteration; of the 2180 unruptured intracranial aneurysms analyzed
(20.1% of the total of unruptured intracranial aneurysms included in the review),
91.8% (99% CI, 90% to 93.2%) were completely occluded, 3.9% (99% CI, 2.9% to
5.2%) had neck remnants, and 4.3% (99% CI, 3.3% to 5.7%) were incompletely
occluded.24 Data on SAH after neurosurgical treatment were available in nine
publications, which included 7.9% of all patients in the review. During the average
follow-up time of 1.2 years per patient, the incidence of hemorrhage was 0.38%.24

ENDOVASCULAR TREATMENT. In the 2018 systematic review and meta-analysis on

complication rates and case fatality risk of endovascular and neurosurgical
treatment of unruptured intracranial aneurysms, 74 studies were included for
the analysis on endovascular treatment outcomes.25 The pooled clinical
complication risk was 4.96% (95% CI, 4.00% to 6.12%), and the case fatality
rate was 0.30% (95% CI, 0.20% to 0.40%), which are comparable to those
established in previous reviews.23,26,27 Factors associated with complications
from endovascular treatment were as follows: female sex (pooled odds ratio,
1.06; 95% CI, 1.01 to 1.11), diabetes mellitus (odds ratio, 1.81; 95% CI, 1.05 to 3.13),
hyperlipidemia (odds ratio, 1.76; 95% CI, 1.3 to 2.37), cardiac comorbidity (odds
ratio, 2.27; 95% CI, 1.53 to 3.37), wide aneurysm neck (>4 mm or dome to neck
ratio >1.5; odds ratio, 1.71; 95% CI, 1.38 to 2.11), posterior circulation aneurysm
(odds ratio, 1.42; 95% CI, 1.15 to 1.74), stent-assisted coiling (odds ratio, 1.82; 95%
CI, 1.16 to 2.85), and stenting (odds ratio, 3.43; 95% CI, 1.45 to 8.09).25 These data
on factors associated with complications from endovascular treatment show that
the use of advanced endovascular methods is associated with an increased risk
of clinical complications. Follow-up imaging after coiling is warranted because
reopening can occur. In a meta-analysis of safety of endovascular treatment,
complete occlusion was found in 86.1% of unruptured intracranial aneurysms.26
Recurrences were found in 24.4% of 1316 patients with unruptured intracranial
aneurysms during a follow-up of 0.4 to 3.2 years. The annual risk of SAH in
patients with endovascular treatment of unruptured intracranial aneurysms was
0.2% (99% CI, 0.1% to 0.3%), although follow-up data were limited (less than
6 months) in 76.7% of patients.26 For elderly patients, endovascular treatment
may be preferred over surgical treatment because a cohort study comparing
2585 patients who had surgical clipping of unruptured intracranial aneurysms
compared with 6120 patients who had endovascular coiling showed that, although
1-year case fatality was not different between the two groups, elderly patients who

484 APRIL 2020

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underwent surgical clipping were more often discharged to a rehabilitation facility KEY POINTS
compared with being discharged home.29
● When deciding whether
Most published observational data on preventive unruptured intracranial to preventively treat
aneurysm treatment are of poor methodological quality, with a nonrandomized unruptured intracranial
nature, with heterogeneous outcome assessment, and without detailed and aneurysms, several factors
standardized recording of procedural clinical complications. Large data sets with should be considered,
including the life
individual patient data are needed to develop and validate prediction scores for
expectancy of the patient,
absolute complication risks and case fatality rates of surgical and endovascular the estimated risk of
treatment. When applying such data in the future, prognostic individualized rupture, the risk of
procedural complication risks according to each person’s risk factor profile can complications of preventive
treatment, and the level of
be developed.
anxiety of the patient with
regard to the knowledge of
Preventive Treatment Versus Observation having an unruptured
The main aims of preventive treatment should be clear when informing patients intracranial aneurysm.
with unruptured intracranial aneurysms about the possibility of preventive
● If an unruptured
treatment. One goal is to prevent SAH, but another is to identify the strategy that intracranial aneurysm is not
best predicts the most quality-adjusted life years for the patient. A complication preventively treated by
from preventive treatment of an unruptured intracranial aneurysm could surgery or endovascular
potentially lead to more impairment of quality of life than an SAH occurring treatment, patients are
often advised to undergo
years later from an untreated unruptured intracranial aneurysm. serial follow-up imaging to
When deciding whether to preventively treat an unruptured intracranial detect aneurysm growth.
aneurysm, several factors should be considered, including the life expectancy of
the patient, the estimated risk of rupture, the risk of complications of preventive
treatment, and the level of anxiety of the patient with regard to the knowledge
of having an unruptured intracranial aneurysm.30,31 Scoring systems on the
risk of rupture, such as the PHASES score,14 can help in the decision making.
Unfortunately, as pointed out earlier, a scoring system to predict the risk of
complications of preventive treatment is not available yet.25 The Unruptured
Intracranial Aneurysm Treatment Score (UIATS) was designed to aid in the
clinical decision making in the management of unruptured intracranial
aneurysms by balancing the risk of rupture against the risk of complications
of preventive treatment.32 The UIATS was developed and validated by an
international multidisciplinary group of 69 specialists consisting of neurosurgeons,
neuroradiologists, neurologists, and clinical epidemiologists. The UIATS can be
used as a comprehensive guide as to how a large group of specialists might manage
an individual patient with an unruptured intracranial aneurysm. However, the
score should only be considered as a starting point in the decision making.
Clinicians should inform patients about the benefits and disadvantages of both
the preventive treatment and the observation strategies, and ultimately patients
decide which strategy they prefer (CASE 12-1).

Observation With Follow-up Imaging

If an unruptured intracranial aneurysm is not preventively treated by surgery or
endovascular treatment, patients are often advised to undergo serial follow-up
imaging to detect aneurysm growth. Imaging can be performed with MR
angiography or CT angiography. MR angiography has the advantage above CT
angiography that no contrast enhancement is needed. Growth is defined as an
enlargement of more than 1 mm in any direction. The strongest risk factor for
rupture is the aneurysm size.14 Consequently, an unruptured intracranial
aneurysm that has grown during follow-up has a higher risk than it had when it

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UNRUPTURED CEREBRAL ANEURYSMS AND ARTERIOVENOUS MALFORMATIONS

was smaller. Moreover, an unruptured intracranial aneurysm that has grown can
be considered an unstable unruptured intracranial aneurysm at risk of aneurysmal
rupture. Several studies reported that unruptured intracranial aneurysms that
grew during follow-up had an increased risk of rupture.33 The largest study
analyzing 1909 unruptured intracranial aneurysms showed growth during
follow-up in 267 and rupture in 18. The risk of rupture of unruptured intracranial
aneurysms that grew during follow-up was 5 times higher than in unruptured
intracranial aneurysms that remained stable.33 If the aneurysm grows, the decision
to not preventively treat the unruptured intracranial aneurysm should be
reconsidered, taking into account the new estimated risk of rupture with the

CASE 12-1 A 55-year-old woman had a CT scan of her brain in the emergency
department after a traumatic head injury. Her past medical history was
significant for hypertension, treated with antihypertensive drugs, and she
had smoked 20 cigarettes per day since the age of 18.
Her blood pressure was 138/88 mm Hg. Her CT scan showed the
suspicion of an incidental finding of an unruptured intracranial aneurysm
of the basilar artery, and additional outpatient CT angiography (CTA) of
the circle of Willis was performed. This CTA confirmed the presence of
an unruptured intracranial aneurysm of the basilar tip with a maximum
diameter of 12 mm and a relatively narrow neck.
Based on the PHASES (Population, Hypertension, Age, Size of aneurysm,
Earlier subarachnoid hemorrhage from another aneurysm, and Site of
aneurysm) score, the patient had an estimated 5-year risk of aneurysm
rupture of 7.2% (PHASES total risk score of 11: 1 point for hypertension,
6 points for the size of the aneurysm [between 10 mm and 19.9 mm], and
4 points for the site of the aneurysm [in the category of anterior cerebral
arteries, posterior communicating artery, and posterior circulation])
(TABLE 12-1).
The patient was very anxious and had problems sleeping after finding
out she had an aneurysm in her brain. She was informed that the aneurysm
could be treated by coiling with an estimated risk of approximately 5%,
which was slightly less than the estimated 5-year risk of aneurysm rupture
of 7.2%. The patient decided to have the aneurysm preventively treated.
She was advised to stop smoking.

COMMENT This case underlines that, when deciding whether to preventively treat an
unruptured intracranial aneurysm, it is important to consider multiple
factors, including the estimated risk of rupture, the risk of complications
of preventive treatment, and the level of anxiety of the patient with regard
to the knowledge of having an unruptured intracranial aneurysm. The
PHASES score can help gain insight into the estimated risk of rupture, which
helps in the decision making.14 In addition, it shows the importance of also
addressing environmental risk factors for the disease. This patient was
advised to stop smoking because smoking is a risk factor for aneurysm
rupture.15

486 APRIL 2020

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growth, the risk of complications of preventive treatment, and the level of anxiety KEY POINTS
the patient feels because of the aneurysm growth.
● The risk of rupture of
Determining the frequency and intervals of follow-up imaging is difficult unruptured intracranial
because aneurysm growth is not constant over time. However, follow-up aneurysms that grew during
imaging within the first year after diagnosing the unruptured intracranial follow-up is higher than in
aneurysm is considered unnecessary because the percentage of unruptured unruptured intracranial
aneurysms that remained
intracranial aneurysms that grow during this time is low.34,35 The absolute 3-year
stable. In the case of
and 5-year risk of aneurysm growth can be predicted by using the ELAPSS growth, the decision not to
(Earlier SAH, Location of the aneurysm, Age, Population, Size of the aneurysm, preventively treat the
and Shape of the aneurysm) score. By using this score, the 3-year risk of growth unruptured intracranial
aneurysm should be
ranges from less than 5% to more than 42% and the 5-year risk from less than
reconsidered.
9% to more than 60%, depending on the risk factors associated with growth
(TABLES 12-2A and 12-2B).33 ● Hypertension should be
treated in patients with an
Medical Management unruptured intracranial
aneurysm, and these
No clinical trials have been performed, so no data exist to support medical patients should be advised
treatment to reduce the risk of rupture. However, because hypertension is a risk to quit smoking.
factor for aneurysm rupture,14 it seems logical to treat hypertension in patients
with unruptured intracranial aneurysms. A small pilot study on 82 patients ● The mortality rate after
hemorrhage from a brain
indeed suggested that antihypertensive medication may help prevent the
arteriovenous malformation
growth and rupture of unruptured intracranial aneurysms.36 In addition, patients has a wide range from 12% to
should be advised to stop smoking because, as already mentioned, smoking is 67%, and, of the patients
a risk factor for aneurysm rupture.15 who survive the
hemorrhage, approximately
45% have severe deficits.
BRAIN ARTERIOVENOUS MALFORMATIONS
The following paragraphs address the risk of hemorrhage for brain AVMs, risk ● The risk of hemorrhage
factors for hemorrhage, preventive treatment options with their associated risks, from a previously
and the approach of treatment versus observation. unruptured brain
arteriovenous malformation
is 1% to 3% per year, and the
Risk of Hemorrhage risk varies depending on
Approximately 10% to 20% of brain AVMs are discovered as incidental findings, the number of risk factors
but patients may also present with neurologic symptoms and deficits. Patients associated with brain
arteriovenous malformation
may have focal or generalized epileptic seizures, headaches, or focal neurologic hemorrhage.
deficits.37,38 Based on data from prospective population-based studies, the
incidence of hemorrhage from a brain AVM is approximately 0.5 per 100,000
persons per year.39–41 Most commonly, hemorrhage from a brain AVM results in
intraparenchymal bleeding, but in about one-fourth of patients subarachnoid or
ventricular hemorrhage may also occur.37 Overall, patients with hemorrhage
from a brain AVM have better outcomes than patients with intracerebral
hemorrhage from other causes, but they still have significant morbidity and
mortality.42 In observational studies, the mortality rate after hemorrhage from a
brain AVM has a wide range from 12% to 67%.42,43 Of the patients who survive
the hemorrhage, approximately 25% have no neurologic deficit, 30% have mild to
moderate deficits, and 45% have severe deficits.44
For a previously unruptured brain AVM, the risk of hemorrhage is low
with hemorrhage rates between 1% and 3% per year.45 Once a brain AVM has
ruptured, the risk of hemorrhage increases twofold to fivefold, which makes
previous hemorrhage the strongest independent risk factor for hemorrhage of
a brain AVM.45,46 However, for the 50% of patients who present with a brain
AVM without hemorrhage, this risk factor does not help in determining the

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UNRUPTURED CEREBRAL ANEURYSMS AND ARTERIOVENOUS MALFORMATIONS

risk of hemorrhage. Risk factors for brain AVM hemorrhage identified within
longitudinal studies vary, which can be explained by small sample sizes or
referral or selection biases of the patients included in the studies. However, it is
important to have insight into the risk factors; a prospective study of follow-up
data on 622 patients with a brain AVM showed that the risk of hemorrhage varies
depending on the number of risk factors that a patient has: from less than 1%
(in the case of no risk factors) to greater than 30% (in case of three risk factors)
per year.47 In this study, increasing age (hazard ratio, 1.05; 95% CI, 1.03 to 1.08),

TABLE 12-2A Risk Factors for Aneurysm Growth According to the ELAPSS Scorea

Risk Factor for Aneurysm Growth Points

Earlier subarachnoid hemorrhage

Yes 0

No 1

Location of aneurysm

Internal carotid artery, anterior cerebral artery, or anterior communicating artery 0

Middle cerebral artery 2

Posterior communicating artery and posterior circulation 4

Age

≤60 years 0

>60 years (per 5 years) 1

Population

North American, Chinese, European (except Finnish) 0

Japanese 1

Finnish 7

Size of aneurysm

1.0–2.9 mm 0

3.0–4.9 mm 4

5.0–6.9 mm 10

7.0–9.9 mm 13

≥10 mm 22

Shape of aneurysm

Regular 0

Irregular 4

ELAPSS = Earlier SAH, Location of the aneurysm, Age, Population, Size of the aneurysm, and Shape of the
aneurysm.
a
Modified with permission from Backes D, et al, Neurology.33 © 2017 American Academy of Neurology.

488 APRIL 2020

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deep brain location (hazard ratio, 3.25; 95% CI, 1.30 to 8.16), and exclusive deep
venous drainage (hazard ratio, 3.25; 95% CI, 1.01 to 5.67) were identified as
independent risk factors for hemorrhage from a brain AVM (TABLE 12-3).47,48
In an individual patient data meta-analysis of four existing cohorts totaling
2525 patients, increasing age (hazard ratio, 1.34 per decade; 95% CI, 1.17 to 1.53)
was confirmed as an independent risk factor for hemorrhage.49 Additional studies
also confirmed deep brain location and exclusive deep venous drainage as risk
factors.45,46 Besides the risk factors of previous hemorrhage, age, deep brain
location, and exclusive deep venous drainage, only race has been identified as an
additional risk factor. In a large combined prospective cohort of 1464 patients,
Hispanic patients with brain AVMs had an almost twofold increased risk of
hemorrhage compared with whites (hazard ratio, 1.9; 95% CI, 1.1 to 3.3)
(TABLE 12-3).48 The size of the nidus of the brain AVM, infratentorial brain AVM
location, associated unruptured aneurysms, and venous dilatations have also
been identified as risk factors but could not be confirmed as independent
risk factors.45,46

Preventive Treatment
For preventive brain AVM treatment, three different modalities are available:
microsurgery, endovascular embolization, and stereotactic radiosurgery
(FIGURE 12-3).50 The main goal of treatment is to prevent hemorrhage; to achieve
this, brain AVMs should be completely obliterated. Partial obliteration does not
reduce the risk of hemorrhage.51 Treatment to control seizures or stabilization of
progressive neurologic deficits may also be considered. The treatment modalities
may be used alone or in combination.52

MICROSURGICAL APPROACHES. Brain AVMs can be treated by microsurgery.

Microsurgery includes a craniotomy, which allows the neurosurgeon to have
adequate exposure to all the vessels of the brain AVM. During the procedure, the
arterial feeders are isolated and divided by dissecting the nidus from the
surrounding brain parenchyma and neurovascular structures. As the last step,

Predicted 3-Year and 5-Year Risk of Aneurysm Growth According to the TABLE 12-2B
ELAPSS Scorea

Risk Score 3-Year Risk of Growth (%) 5-Year Risk of Growth (%)
<5 5 8

5–9 8 13

10–14 12 19

15–19 18 28

20–24 26 40

≥25 43 61

ELAPSS = Earlier SAH, Location of the aneurysm, Age, Population, Size of the aneurysm, and Shape of the
aneurysm.
a
Modified with permission from Backes D, et al, Neurology.33 © 2017 American Academy of Neurology.

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UNRUPTURED CEREBRAL ANEURYSMS AND ARTERIOVENOUS MALFORMATIONS

the venous outflow is disconnected. Microsurgery results in a high rate of

complete nidus obliteration and immediate elimination of the hemorrhage risk
but also carries a risk of complications.
The Spetzler-Martin grading scale is widely used to determine the risk of
postoperative neurologic deficits or death as a result of microsurgical dissection
of a brain AVM.53 It categorizes brain AVMs into five grades based on size (small,
0 to 3 cm; medium, 3 to 6 cm; large, >6 cm), existence of deep venous drainage,
and eloquence of location (TABLE 12-4).54 In a large, single-center series of
patients with unruptured brain AVMs, the risk of a permanent deficit after
microsurgery was only 2% for Spetzler-Martin grade 1 or 2 lesions, although this
risk increased to 17% for grade 3 lesions and to 45% for grade 4 or 5 lesions.55
Other studies showed similar results with 2% morbidity and 0.3% mortality in
patients with grade 1 or 2 lesions.56,57 Angiographic cure rates have been shown to
be very high for all different Spetzler-Martin grades, ranging from 95% to 99%.56
Although the Spetzler-Martin grading scale is helpful in the prediction of
surgical outcomes, it also has limitations because many factors that potentially
influence outcome are not included in the scale. Therefore, in 2010, a new
grading scale was proposed by Lawton and colleagues54 aimed at more accurately
predicting surgical risk. The supplementary Spetzler-Martin, or Lawton-Young,
grading scale adds patient age, history of hemorrhage, and nidus type to the
classic Spetzler-Martin scale factors.54 This grading system is an addition to
the Spetzler-Martin grading scale, not a replacement for it. Lower grades (lower
total points) indicate lower risk of treatment. Patients with supplementary
Spetzler-Martin grades 2 and 3 have up to 2% risk of neurologic deficits, whereas
this risk increases to 10% for supplementary Spetzler-Martin grade 4 and to 63%
for grade 8.58 Studies have shown that the supplementary Spetzler-Martin scale
improves the outcome prediction accuracy better after surgery than the
Spetzler-Martin grading scale.54,58–60

ENDOVASCULAR EMBOLIZATION THERAPY. For endovascular embolization,

microcatheters are used to deliver embolic materials to feeding arteries or the
nidus. Different embolization techniques and materials are used and include
ethylene vinyl alcohol, N-butyl cyanoacrylate, polyvinyl alcohol particles, and
coils, which may be used alone or in combination. Embolization is used to
occlude brain AVMs but may also be used as primary treatment for intranidal
aneurysms.61 Occasionally, when brain AVMs are thought to cause focal

TABLE 12-3 Risk Factors for Rupture of Brain Arteriovenous Malformations

Size Effect Hazard Ratio

Risk Factor (95% Confidence Interval)

Previous hemorrhage from brain arteriovenous malformation 3.86 (2.42–6.14)47

Age 1.05 (1.03–1.08)47

Hispanic ethnicity 1.9 (1.1–3.3)48

Deep brain location 3.25 (1.30–8.16)47

Exclusive deep venous drainage 3.25 (1.01–5.67)47

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neurologic deficits as a consequence KEY POINTS
of vascular steal or local venous
● Risk factors associated
hypertension, endovascular embolization with brain arteriovenous
of select, high-flow feeders may decrease malformation hemorrhage
steal or venous hypertension.62 For large are previous hemorrhage,
brain AVMs, staged treatment with more race, age, deep brain
location, and exclusive deep
than one embolization session may be
venous drainage.
needed. In the case of endovascular
embolization, intracerebral hemorrhage ● Brain arteriovenous
and ischemic stroke are the two most malformations can be
common complications.63 Ischemic stroke preventively treated by
microsurgery, endovascular
can be caused by thromboembolic embolization, and
complications of the catheterization and stereotactic radiosurgery.
by embolization of vessels not being part Each treatment has a risk of
of the brain AVM. Brain hemorrhage can complications, and different
factors associated with an
be caused by injury of the vessel wall or by increased risk have been
periprocedural brain AVM rupture.64 In a identified.
retrospective study of 377 endovascular
embolization procedures in 202 patients, ● The main goal of
treatment is to prevent
the following factors associated with new
hemorrhage from the brain
deficits after treatment were identified: arteriovenous malformation,
more than one embolization session, brain but treatment to control
AVM diameter greater than 3 cm, brain seizures or stabilization of
progressive neurologic
AVM diameter greater than 6 cm, deep
deficits caused by the brain
venous drainage, and eloquent location.65 arteriovenous malformation
By using these variables, a scale of 0 to 4 may also be considered.
points was developed with higher scores
having an increased risk of a neurologic ● Microsurgery,
endovascular embolization,
deficit.65 This scale has not been validated and stereotactic
in a prospective cohort. Interestingly, the radiosurgery are often
variables associated with increased risk of combined to optimally treat
deficits are comparable to those of the brain arteriovenous
malformations.
Spetzler-Martin grading scale.53 In a 2019
systematic review, 15 studies with
597 patients and 598 brain AVMs treated
with embolization were analyzed.66
Thirty-four percent of brain AVMs had a FIGURE 12-3
The three different treatment
Spetzler-Martin grade 3. Complete modalities to preventively treat brain
obliteration was reported in 45.8% of brain arteriovenous malformations:
AVMs. The overall clinical complication microsurgery (A), endovascular
rate was 24.1% with the most common embolization (B), and stereotactic
radiosurgery (C).
complication being intracerebral Modified with permission from Solomon RA
hemorrhage in 9.7% of the patients. and Connolly ES Jr, N Engl J Med.50
Mortality of the endovascular © 2017 Massachusetts Medical Society.
embolization was 1.5%.66

STEREOTACTIC RADIOSURGERY. Stereotactic radiosurgery involves the precise,

image-guided delivery of high-energy beams of photons or protons to a defined
volume containing the brain AVM nidus, which induces gradual sclerosis of the
blood vessels and thrombosis of the lesion.67 The primary goal of stereotactic

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UNRUPTURED CEREBRAL ANEURYSMS AND ARTERIOVENOUS MALFORMATIONS

radiosurgery is obliteration of the brain AVM to prevent hemorrhage in the

future. Secondary goals of radiosurgery may be to preserve or to improve
neurologic function, including reducing epileptic seizures or neurologic deficits
caused by the brain AVM.68 A decrease of epileptic seizures is observed in patients
with a reduction or with complete obliteration of the brain AVM nidus after
radiosurgery.69 Neurologic function may also improve after radiosurgery.70
One of the greatest limitations of stereotactic radiosurgery is the delay in the
obliteration of the brain AVM, which can take up to 2 to 4 years; this delay is
referred to as the latency period. Most data suggest that the risk of bleeding

TABLE 12-4 Spetzler-Martin and Lawton-Young Grading Scales for Brain Arteriovenous
Malformationsa

Lesion Characteristic Pointsb

Spetzler-Martin grading scale53 (maximum score = 5)

Size

Small (<3 cm) 1

Medium (3–6 cm) 2

Large (>6 cm) 3

Location

Noneloquent 0

Eloquent 1

Veins

Superficial 0

Deep 1

Lawton-Young grading scale54 (maximum score = 5)

Age

<20 years 1

20–40 years 2

>40 years 3

Bleeding

Yes 0

No 1

Compactness

Yes 0

No 1

a
Modified with permission from Lawton MT, et al, Neurosurgery.54 © 2010 Oxford University Press.
b
Lower grades (lower total points) indicate a lower risk of surgical treatment.

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during this latency period is comparable to the risk during the period before KEY POINT
treatment.71,72 Follow-up studies demonstrate obliteration in 70% to 80% of
● Follow-up imaging can
brain AVMs after stereotactic radiosurgery.73,74 In a study on predictive factors take place after treatment
for obliteration in 139 patients after radiosurgery, brain AVM size (odds ratio, of a brain arteriovenous
0.88; 95% CI, 0.81 to 0.96), noneloquent location (odds ratio, 3.2; 95% CI, 1.29 to malformation to ensure that
7.93), low-flow pattern (odds ratio, 3.47; 95% CI, 1.6 to 7.53), and an absence of it is completely obliterated.
This imaging is certainly
perinidal angiogenesis (odds ratio, 2.61; 95% CI, 1.21 to 5.64) were identified as
indicated after embolization
predictive factors.75 Besides the risk of bleeding after radiosurgery, other and radiosurgery.
complications may include radiation-induced necrosis, edema, and cyst
formation, which can develop even long after treatment.76,77 Most studies on
stereotactic radiosurgery are single-center, retrospective cohort studies, and
these studies show that stereotactic radiosurgery can be well applied in brain
AVMs with a small to moderate size that are generally less than 12 cm3 in volume
or less than 3 cm in maximum diameter.70,73,74 In a cohort of 509 patients from
seven different institutions treated with stereotactic radiosurgery, adverse
neurologic outcome, defined as any new or worsening neurologic symptoms or
death, was observed in 13% of patients.73 As the Spetzler-Martin grading scale
was developed to predict the surgical outcomes of brain AVMs, radiosurgical
outcome can be predicted with the Virginia Radiosurgery AVM Scale (VRAS).70,
78
In the VRAS, patients are assigned 1 point each for having a brain AVM volume
of 2 to 4 cm3, an eloquent brain AVM location, or a history of hemorrhage and 2
points for having a brain AVM volume greater than 4 cm3. Eighty percent of
patients who had a score of 0 or 1 point had a favorable outcome, as did 70% who
had a score of 2 points and 45% who had a score of 3 or 4 points.70
As already indicated, the three different treatment modalities, microsurgery,
endovascular embolization, and stereotactic radiosurgery, are often combined to
optimally treat brain AVMs. Microsurgery can be preceded by endovascular
embolization, thereby reducing the risk of bleeding during surgery and
facilitating complete resection of the brain AVM. Stereotactic radiosurgery may
be performed after embolization to reduce nidal volumes or improve nidal
obliteration or both. Endovascular embolization can be an effective addition to
both radiosurgery and surgery. Endovascular embolization may be used before
radiosurgery to reduce the nidus size of large brain AVMs, because they have a
lower cure rate with radiosurgery alone. Embolization before surgery may be
used to reduce blood loss and to occlude vessels that may be difficult to handle
during surgery.
Follow-up imaging can take place after treatment of a brain AVM to ensure
that it is completely obliterated. This imaging is certainly indicated after
embolization and radiosurgery and can also identify the delayed effect of the
treatment, which is especially important after stereotactic radiosurgery.
Angiography is necessary to confirm complete obliteration.

Preventive Treatment Versus Observation

ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations)79
compared clinical outcomes among patients with unruptured brain AVMs that
were managed either with medical therapy alone or with medical therapy
plus preventive interventional therapy (surgery, endovascular therapy, or
radiotherapy, alone or in any combination).80 Based on the results of a planned
interim analysis, the data and safety monitoring board advised to end the
randomization phase of the trial because the interim analysis showed that

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UNRUPTURED CEREBRAL ANEURYSMS AND ARTERIOVENOUS MALFORMATIONS
KEY POINTS
● Patients with brain
arteriovenous
malformations have a higher
rate of neurologic morbidity
and mortality after
preventive interventional
therapy compared with
observation. These data
indicate that patients with
unruptured asymptomatic
brain arteriovenous
malformations should be
observed. However, in the
case of unruptured
symptomatic arteriovenous
malformations, treatment
may be considered to
reduce epileptic seizures or
neurologic deficits caused
by the arteriovenous
malformations.
● Evidence to support the
use of imaging to screen
and monitor patients
with unruptured
brain arteriovenous
malformations is lacking.
● No medical treatment
is available to treat
brain arteriovenous
malformations or to reduce
the risk of hemorrhage
from them.
494
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
preventive interventional therapy was associated with a statistically significant
higher risk of death or symptomatic stroke (hazard ratio, 3.7; 95% CI, 1.85 to 7.14)
and a higher risk of serious neurologic deficits (rate ratio, 2.77; 95% CI, 1.20 to
6.25) than medical therapy alone.80 For the long-term follow-up with a median
of 33 months in ARUBA, the rate of death or stroke with functional impairment
was statistically significantly lower for patients receiving medical therapy
alone than for those with preventive interventional therapy.80 These data further
show that patients with a brain AVM have a higher rate of neurologic morbidity
and mortality after preventive interventional therapy.80 Moreover, a prospective
population-based outcome study on patients with unruptured brain AVMs
showed comparable results; the use of conservative management was associated
with better clinical outcomes for up to 12 years than preventive interventional
therapy.81 Criticism of the ARUBA trial exists, including the relatively short
follow-up time with a mean of 33.3 months, potential selection bias of the
patients, the heterogeneity of the treatment modalities used in the intervention
arm, and the high rate of brain AVM hemorrhage of 25% in treated patients in the
interventional arm.82 However, despite these criticisms of the ARUBA trial, it is
now generally recommended that patients with unruptured asymptomatic brain
AVMs should be observed. As already described, the different treatment
modalities may, however, be used to reduce epileptic seizures or neurologic
deficits caused by brain AVMs.62,68,69
Evidence to support the use of imaging to screen and monitor patients with
brain AVMs is lacking. However, for patients who are treated conservatively,
MRI examinations every 5 years have been recommended to detect silent
hemorrhages unless new symptoms necessitate an earlier examination.83 CT
angiography and digital subtraction angiography have no role in the routine
follow-up care of patients who are clinically stable.
Medical Management
Currently, no medical treatment is available to treat brain AVMs or to reduce the
risk of hemorrhage from them. However, associated seizures can be managed
with antiepileptic drugs, and headaches can be managed with preventive or acute
symptomatic treatment.
CONCLUSION
If an unruptured intracranial aneurysm or unruptured brain AVM is detected,
physicians must work with patients to decide whether to preventively treat the
lesion to prevent hemorrhage from it in the future. The consequences of bleeding
from unruptured intracranial aneurysms and brain AVMs are severe with a high
likelihood of morbidity and mortality. Depending on the number of different risk
factors associated with aneurysm rupture, the 5-year risk of rupture of
unruptured intracranial aneurysms ranges from 0.25% to more than 15%. The
risk of hemorrhage from previously unruptured brain AVMs is 1% to 3% per year
and varies depending on the number of risk factors associated with brain AVM
hemorrhage. Unruptured intracranial aneurysms can be preventively treated by
surgical clipping or endovascular coiling and brain AVMs by microsurgery,
endovascular embolization, and stereotactic radiosurgery. For brain AVMs,
different treatment modalities are often combined for optimal treatment. All
treatments have a risk of complications, and factors associated with increased
APRIL 2020
risk are known. Management is aimed at determining the risk of future
hemorrhage compared with the risk of intervention.
The decision regarding whether to preventively treat an unruptured
intracranial aneurysm with an interventional procedure is complex, and
different factors should be considered, including the life expectancy of the
patient, the estimated risk of rupture, the risk of complications of preventive
treatment, and the level of the patient’s anxiety about the unruptured
intracranial aneurysm. A randomized clinical trial and prospective follow-up
data have shown that preventive interventional therapy in patients with a brain
AVM is associated with a higher rate of neurologic morbidity and mortality
compared with observation. Therefore, it is recommended that patients with
unruptured asymptomatic brain AVMs should be observed. However, in the case
of unruptured symptomatic AVMs, treatment may be considered to reduce
epileptic seizures or neurologic deficits caused by the AVMs.

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