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Cerebral Arteriovenous Malformation Diagnosis and Management

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DOI: 10.1055/s-0033-1364212 · Source: PubMed

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468

Cerebral Arteriovenous Malformation Diagnosis

and Management
Kaiz Asif, MD1 John Leschke, MD1 Marc A. Lazzaro, MD1,2

1 Departments of Neurology, Medical College of Wisconsin and Address for correspondence Marc A. Lazzaro, MD, Department of
Froedtert Hospital, Milwaukee, Wisconsin Neurology and Neurosurgery, Division of Neurointervention, Medical
2 Departments of Neurosurgery, Medical College of Wisconsin and College of Wisconsin/Froedtert Hospital, Milwaukee, WI
Froedtert Hospital, Milwaukee, Wisconsin (e-mail: mlazzaro@mcw.edu).

Semin Neurol 2013;33:468–475.

Abstract Arteriovenous malformations of the brain can carry considerable morbidity and
Keywords mortality in the setting of rupture. The complex angioarchitecture and hemodynamic
► arteriovenous alteration requires careful consideration in diagnostic and management approaches. In
malformation this review, the authors define the pathophysiology, outline diagnostic methods, and
► radiosurgery highlight current management approaches.
► embolization
► hemorrhagic stroke

An arteriovenous malformation (AVM) consists of a complex
tangled web of single or multiple arteries linked to single or
multiple draining veins through an abnormal intervening
network of vessels.1–3
Although AVMs are rare, the associated high morbidity and
mortality underscores the need for careful consideration in
diagnosis and management of these vascular abnormalities.
Specifically, an understanding of the pathophysiology, hemo-
dynamic disturbance, imaging features, and treatment op-
tions is necessary.
Biology, Pathophysiology, and
Hemodynamics
Fundamentally, AVMs are congenital vascular lesions that
arise from a disruption of normal vascular morphogenesis
during fetal development.4 Arteriovenous malformations are
deficient in an intervening capillary bed, but the precise
mechanism of pathogenesis remains unknown. Vascular
morphogenesis proceeds in two stages embryologically. Vas-
culogenesis occurs initially as endothelial cells arise from
angioblasts to form a primary vascular plexus. Angiogenesis
occurs thereafter with remodeling and organization of the
primary vascular plexus mediated by a complex array of
protein signaling pathways.5–9
Clinical and laboratory observations offer a collection of
theories describing this pathological progression. Some sug-
gest that AVMs represent a persistence of the congenital
vascular plexus with failure of the necessary venous/arterial
remodeling.10 The fact that almost half of AVMs are located in
arterial borderzone territories can be explained by the theory
that AVMs may arise from persistent artery to artery con-
nections during the lissencephalic state in the primitive
cortex.11 In the normal state, these connections regress as
the cortical architecture develops and the gyri are formed,
ultimately giving rise to the leptomeningeal system; hence,
AVMs are thought to arise within or after the formation of
arterial border zones.12 Others have suggested that AVMs are
dynamic in nature and a product of a proliferative capillar-
opathy.13 Arteriovenous malformations might even represent
fistulized cerebral venous angiomas.14–16
Arteriovenous malformations can be located anywhere
throughout the cerebral vascular system. They can be restrict-
ed to the dura or choroid plexus and can vary widely in size,
such that some require microscopy for visualization, but
others can involve an entire hemisphere. The distal arterial
branches are more commonly involved, predominantly in-
volving the distribution of the middle cerebral artery and the
hemispheric convexities.17 Generally, AVMs manifest as soli-
tary lesions; multiple lesions are relatively rare. Multiple

Issue Theme Advanced Cerebrovascular Copyright © 2013 by Thieme Medical DOI http://dx.doi.org/
Disease Management; Guest Editor, Jason Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0033-1364212.
Mackey, MD, MS New York, NY 10001, USA. ISSN 0271-8235.
Tel: +1(212) 584-4662.
 Cerebral Arteriovenous Malformation Diagnosis and Management
lesions rarely occur spontaneously and are most commonly
observed in syndromic settings with cutaneous or extracra-
nial vascular anomalies18 such as Rendu-Osler-Weber disease
and Wyburn-Mason syndrome.
Brain AVMs are often pyramid-shaped such that the base is
adjacent the cortex and the vertex projects internally toward
the ventricles. Arteriovenous malformations are further dif-
ferentiated anatomically based on the involvement of brain
parenchyma. A compact nidus is a malformed capillary bed
that is tightly organized such that normal brain parenchyma
is displaced. A diffuse nidus is loosely organized with sparse,
abnormal AV channels such that normal brain parenchyma
persists.19 The appearance of an AVM on catheter angiogra-
phy can highlight these characteristics (►Fig. 1).
The velocity of blood flow is considerably higher through
AVMs than through normal brain parenchyma. As a result of
Fig. 1 A high-frame-rate catheter angiogram captures several distinct
components of an arteriovenous malformation including feeding
artery supply (A, arrows), nidus (B, circle), and venous outflow
(C, arrow ), which must be separated by fractions of a second due to the
high flow.
Asif et al. 469
the abnormal hemodynamic condition, feeding arteries and
draining veins become progressively dilated and tortuous.
Normal vascular structures undergo a series of secondary
changes. Feeding arteries may be one or numerous and
experience high flow arteriovenous shunting due to absence
of capillary networks. Because of constant intraluminal stress
there is abnormal dilation, degenerative changes with aber-
rant elastic lamina, variability of medial thickness in the
vessel wall, and architectural disarray.2,20–22 High flow may
result in new pathology such as saccular aneurysm formation.
These aneurysms can be located at the level of the circle of
Willis, the feeding arteries, or within the nidus.23–26 Addi-
tionally, high flow can produce progressive stenosis and
eventual occlusion of feeding arteries.27 Draining veins can
be single or multiple, deep or cortical, and are also exposed to
increased intraluminal stress. Direct shunting of blood at
arterial pressure causes dilatation, thickening, and tortuosity
in the involved veins. High flow may also produce localized
stenosis, frequently at the level where the veins cross the dura
to reach the sinus,28,29 and secondary venous aneurysmal
dilatation.30
Epidemiology
Establishing a true prevalence of AVM is difficult because of
the rarity of the disease and the presence of asymptomatic
patients; prevalences are likely underestimates. Large post-
mortem studies are still needed. Only a few hospital-based
postmortem studies are available, reporting a prevalence
between 400 and 600 per 100,000.22,31,32 Much of what is
known about incidence is from population-based studies.
Over a 10-year-period in the Netherlands Antilles, the annual
incidence of symptomatic AVMs was 1.1 per 100,000 per
year.33 In another study, the incidence of symptomatic AVMs
was 1.84 per 100,000 per year.34 The New York Islands AVM
Study, a prospective population-based incidence and case-
control study, found an annual AVM detection rate of 1.34 per
100,000 person-years. Arteriovenous malformations are
found incidentally on 0.05% of brain magnetic resonance
imaging (MRI) screens.35 There are very few familial cases.
Arteriovenous malformations are more commonly identified
in younger individuals. Detection in utero or in infancy is
rare,36–38 and the diagnosis is most commonly made between
30 and 40 years of age. Both sexes are affected in nearly equal
proportions.33,39
Clinical Presentation
The clinical presentation of these lesions can vary and
include signs of intracranial hemorrhage (focal deficits,
nausea, vomiting, etc.), seizures, and headaches. Intracra-
nial hemorrhage is a common cause of symptomatic pre-
sentation,40 and often is the presenting feature in the
second through fourth decades of life.41 Seizures at pre-
sentation have been reported to occur in ! 30% of patients.
Headaches have been reported in 14% of patients.39 The
clinical presentation may be affected by the size and loca-
tion of the lesion.
Seminars in Neurology Vol. 33 No. 5/2013
470 Cerebral Arteriovenous Malformation Diagnosis and Management Asif et al.

Diagnosis intranidal gliosis, parenchymal atrophy with focal dilatation

The diagnosis of an AVM is usually made via noninvasive
imaging (computed tomography [CT] or MRI), but the thera-
peutically relevant anatomical and functional information
often requires catheter cerebral angiography.
of the ventricular system, presence of an old hematoma
(hemosiderin on gradient echo [GRE] sequences), hydroceph-
alus in cases of prior hemorrhage, and ventricular system
compression by enlarged draining veins.45,46 Multimodal
imaging is often necessary to confirm a diagnosis of AVM
as demonstrated in ►Fig. 2.

Computed Tomography and Magnetic

Resonance Imaging
Because the most common clinical manifestations are not
specific for AVM, the first imaging modality is usually a
noncontrast CT. Certain factors would warrant further evalu-
ation for an AVM in a patient who presents with spontaneous
intracranial hemorrhage. Young patients with lobar paren-
chymal hematoma or otherwise unexplained intraventricular
hemorrhage or subarachnoid hemorrhage require additional
imaging. Findings of curvilinear or speckled calcifications and
serpiginous hyperdense structures can represent draining
veins, components of the nidus, or dilated arterial
feeders.39,42–44 Confirmation of the diagnosis and evaluation
of the vascular and parenchymal details is necessary. Al-
though a CT angiogram could provide better vascular details,
an MRI with an MRA might allow better visualization of
parenchymal changes. Magnetic resonance imaging can allow
evaluation of eloquence of the involved brain, perinidal or
Digital Subtraction Angiography
Digital subtraction angiography (DSA) is considered the
gold standard for the evaluation of cerebral AVMs. Although
noninvasive imaging provides structural understanding of
an AVM, pretherapeutic planning often necessitates DSA to
allow excellent spatial as well as temporal resolution,
which is required for assessing the nidus size, assessing
feeding arterial and draining venous stenosis, and evaluat-
ing for flow-related arterial and intranidal aneurysms and
draining venous aneurysms.47 Moreover, planning of en-
dovascular embolization can be performed using super-
selective microcatheter angiography, which allows
targeting of specific feeding arterial branches and further
angioarchitecture characterization. The addition of three-
dimensional (3D) rotational angiography to DSA aids in
understanding complex 3D characteristics and allows
superior determination of the radiation target if radiosur-
gery is planned.48,49

Fig. 2 (A) Diagnostic imaging for evaluation of suspected right frontal arteriovenous malformation (AVM) shows hemorrhage on a noncontrast
head computed tomography (CT) scan. (B) Magnetic resonance (MRI) brain T2 sequence image demonstrates flow voids adjacent to the
hemorrhage consistent with an AVM nidus. (C) Catheter angiography defines the angioarchitecture of the lesion. (D–G) Sequential frames in a
lateral projection angiogram of the right frontal AVM show abnormal artery architecture arising from the right pericallosal artery with early
cortical vein filling and rapid outflow through the superior sagittal sinus.

Seminars in Neurology Vol. 33 No. 5/2013

 Cerebral Arteriovenous Malformation Diagnosis and Management
Functional Imaging
Assessment of the eloquence of brain tissue involved with
AVMs with blood-oxygen-level dependent (BOLD) functional
MRI could help in avoiding damage to the eloquent brain
areas before embolization, surgical resection, or radiosurgery.
In this way BOLD can help shorten the surgical time and
achieve smaller craniotomies.50,51 One of the major limita-
tions of the task-based functional MRI for AVMs and vascular
tumors is the phenomenon of neurovascular uncoupling,
which occurs when dysplastic vessels do not demonstrate
appropriate BOLD activation of the normal functioning
neurons.52
Natural History
For unruptured AVMs, the rate of rupture has not been well-
defined, though reports include annual risks of up to 2 to 4% in
patients with an initial nonhemorrhagic presentation and a
widely varying lifetime risk of hemorrhage estimated to be 17
to 90%.53 High-risk features for rupture including nidal
aneurysms and angiographic flow characteristics are often
considered, but consensus on the importance of these fea-
tures has not been established. For ruptured AVMs, the risk of
rehemorrhage after first hemorrhagic presentation has been
reported as 6 to 18% in the first year, after which it is ! 2% per
year for the next 20 years.54
Classification Systems
The Spetzler-Martin classification is used to grade AVMs
based on their degree of surgical difficulty and the risk of
surgical morbidity and mortality. The grade is based on the
size of the AVM (< 3 cm: 1 point, 3–6 cm: 2 points, > 6 cm: 3
points), venous drainage (superficial only: 0 points, deep: 1
point) and eloquence of adjacent brain (eloquent: 0 points,
noneloquent: 1 point), with grades ranging from I to V.
Arteriovenous malformations too complex for resection, in-
cluding brainstem and holohemispheric AVMs, were given
grade VI. Low-grade AVMs (grades I and II) have relatively low
surgical morbidity rates and are commonly treated surgically,
while high-grade AVMs (grades IV and V) have relatively high
surgical morbidity rates and are commonly managed
conservatively.
Grade III AVMs are somewhat more challenging and are
the most heterogeneous of the five grades.55 Grade III AVMs
have been further divided into four different combinations:
small-deep-eloquent (S1V1E1), medium-deep (S2V1E0), me-
dium-eloquent (S2V0E1), and large (S3V0E0). Based on a
consecutive series of 76 grade III AVMs, Lawton et al found
that neurologic outcomes varied according to the subtype of
grade III AVM. They found that small-deep-eloquent (S1V1E1)
AVMs had surgical risks similar to low-grade AVMs, but that
medium-eloquent (S2V0E1) AVMs had surgical risks similar
to high-grade AVMs. Medium-deep (S2V1E0) had intermedi-
ate surgical risks.56
Lawton and colleagues subsequently introduced a supple-
mentary grading system to the Spetzler-Martin grading sys-
Asif et al. 471
tem. It added three more variables: Age (< 20 years: 1 point,
20–40 years: 2 points, > 40 years: 3 points), prior history of
rupture (ruptured: 0 points, not ruptured: 1 point), degree of
diffuseness (compact: 1 point, diffuse: 0 point) with grades
ranging from I to V. They analyzed a consecutive surgical
series of 300 patients to compare the predictive accuracy
using the Spetzler-Martin scale and the supplementary scale
and found the scale had high predictive accuracy and strati-
fied surgical risk more evenly. The supplementary grade can
be considered separately, with supplementary grades I to III
having an acceptably low risk of AVM resection. The supple-
mentary scale can also be added to the Spetzler-Martin grade,
with combined grades 1 to 6 having an acceptably low
surgical morbidity. In cases of mismatched Spetzler-Martin
and supplementary grades, the supplementary grading sys-
tem can potentially play a role in altering clinical decisions,
though more data on the application of this grading system is
required.57
A separate classification system for grading in endovas-
cular therapy has also been proposed. This classification
system includes AVM size, number of feeding arteries, and
pial versus perforating feeding arteries. Low-grade AVMs that
were considered suitable for endovascular therapy were
small, had fewer than two feeding arteries, and were not
supplied by perforators, whereas high-grade AVMs that were
large (> 4 cm), had more than four feeding arteries, and were
supplied by perforators were not suitable for endovascular
therapy.58
Management
Due to the lack of robust natural-history data and the limited
understanding of features thought to be associated with a
high risk of hemorrhage, the management of AVMs remains
complex. The choice between procedural management and
observation with medical management and radiologic sur-
veillance is not always clear-cut. The high morbidity and
mortality associated with ruptured AVMs often warrants a
procedural approach, with the goal of AVM eradication.
Treatment modalities include endovascular embolization,
surgical resection, and radiosurgical intervention. Random-
ized studies comparing treatment approaches are lacking.
The specifics of each case are considered and a tailored team-
based approach is often required.
Observation
Unruptured AVMs with a nonhemorrhagic presentation are
often considered for observation, which includes medical
management and surveillance imaging. The ARUBA (A Ran-
domized Trial of Unruptured Brain Arteriovenous Malforma-
tions) Trial compared medical management with invasive
treatment in patients with unruptured AVMs. The ARUBA
Trial halted enrollment after a preplanned interim data safety
monitoring board review identified a higher event rate in the
intervention group compared with medical management.59
Although early event rates were higher in the intervention
arm, patients will be followed to determine whether the
difference in stroke and death in the two arms changes
Seminars in Neurology Vol. 33 No. 5/2013
472 Cerebral Arteriovenous Malformation Diagnosis and Management Asif et al.

over time. Medical management for symptomatic unruptured

AVMs includes anticonvulsants in patients with seizures,
medications for headache, and optimization of blood pressure
control. Surveillance imaging is performed to evaluate for
changes in AVM size and morphology, though the optimal
surveillance strategy is unclear. Surveillance is commonly
performed on a yearly or biennial basis.

Endovascular Treatment
With the advent of improved endovascular technology, so-
phisticated microcatheter designs, and embolic materials with
desirable properties, endovascular embolization of AVMs has
become increasingly common. The goal of endovascular ther-
apy is to achieve complete cure in small AVMs with favorable
characteristics for an endovascular approach, or for partial
targeted embolization in conjunction with surgical resection
or in combination with stereotactic radiotherapy. Emboliza-
tion materials include liquid embolics, such as n-butyl cyano-
acrylate and ethylene vinyl alcohol copolymer (Onyx), and
platinum embolic coils. Feasibility of endovascular treatment
depends on the angioarchitecture of the AVM, with small size Fig. 3 Lateral projection angiogram images demonstrate a large left
and a single feeding artery being favorable features for com- parieto-occipital arteriovenous malformation (A) with near-complete
obliteration following liquid embolization (B).
plete curative embolization. Although it is technically demand-
ing to catheterize a large number of small, minimally dilated
feeding arteries, advanced microcatheter designs and flow- Partial targeted embolization is preferred for larger AVMs.
guided ultrathin microcatheters have allowed delivery beyond For presurgical embolization, the goal is to reduce the size of
tortuous anatomy (►Fig. 3). Complete cure of the AVM has the AVM and to embolize deep feeding vessels, which would
been reported in up to 20% of cases.60 be difficult to access surgically. When combined with

Fig. 4 Magnetic resonance brain T2 sequence images (MRIs) show a large left basal ganglia arteriovenous malformation (AVM) with an enlarged
left internal cerebral vein at diagnosis (A). Follow-up MRI at 1 year (B) and 2 years (C) after radiosurgery show significant progressive reduction in
the AVM nidus. Lateral projection catheter angiogram images for radiosurgery targeting at diagnosis demonstrate arteriovenous shunting
through the left basal ganglia AVM (D–G).

Seminars in Neurology Vol. 33 No. 5/2013

 Cerebral Arteriovenous Malformation Diagnosis and Management
Table 1 Treatment approaches for cerebral arteriovenous malformations
Approach
Endovascular Catheter delivery of
embolization
• Liquid embolics (n-butyl
cyanoacrylate glue, Onyx)
• Coils
Surgical resection Microsurgical excision
Radiotherapy Focal radiation is administered
to the lesion
radiosurgery, the target of embolization is often the periph-
ery of the AVM to reduce the size and therefore the total
radiation dose required.61,62 Clinically significant complica-
tions have been reported to occur in ! 6.5% cases.63
Surgical Resection
Microsurgical excision involves creating a craniotomy cen-
tered over the nidus followed by careful devascularization of
the AVM by occluding the arterial feeders. Circumferential
separation of the AVM from the adjacent parenchyma is
performed and the draining veins are then divided.64 Intra-
operative electrophysiologic monitoring is often performed
using electroencephalography, somatosensory evoked poten-
tials, and in the case of posterior fossa AVMs, brainstem
auditory evoked potentials.65 Postoperative angiography is
performed to confirm complete excision.
The risk of microsurgical approach is assessed using the
Spetzler-Martin grading system with higher grades associat-
ed with greater surgical morbidity and mortality.55,66 A meta-
analysis reviewing several series from 1990 to 2000 showed a
mean global mortality of 3.3% and mean postoperative global
morbidity of 8.6%.67
Stereotactic Radiotherapy
Stereotactic radiosurgery aims at achieving progressive oblit-
eration of an AVM using intense high-dose radiation pro-
duced by a radiation source (including gamma knife, linear
accelerators, or proton-beam) and delivered accurately and
precisely using a navigation system (►Fig. 4). Obliteration of
the AVM occurs via endothelial damage and thickening of
intimal layer followed by thrombosis and necrosis of AVM
vessels,68 a process which takes ! 2 to 3 years with a median
of !2 0 months required to obtain subtotal (> 95%) oblitera-
tion.69,70 The nidus geometry and neighboring at-risk struc-
tures are determined using thin-slice MRI and CT, which are
used to formulate radiosurgery treatment plans.
Successful obliteration with radiosurgery is dependent on
various factors, including nidus volume, nidus density, radia-
tion dose, and location.71 The modified radiosurgery-based
grading scale incorporates some of these factors and is
calculated as follows: (0.1 " volume in mL) þ (0.02 " age
in years) þ (0.5 " location [0 for hemispheric/intraventricu-
lar/callosal/cerebellar AVMs and 1 for AVMs involving the
Asif et al. 473
Benefits Limitations
Minimally invasive Obliteration rate can be
Real-time angiography lower depending on characteristics
Risk of ischemic complications
during treatment
High rates of complete Invasive due to craniotomy
obliteration
Noninvasive 1–3 year latency for obliteration
Parenchymal radiation injury
Limited to smaller lesions
thalamus/basal ganglia/brainstem]).72 The proportion of
AVMs obliterated without a new neurologic deficit was
greater than 90% for a score less than 1 and less than 40%
for a score more than 2.73
Various approaches for treatment of AVMs continue to
develop and often involve complementary interventions in
complex lesions to afford a greater success rate (►Table 1).
Conclusions
Arteriovenous malformations are rare developmental vascu-
lar lesions that often present in younger individuals with
intracranial hemorrhage, seizure, or headaches. Rates of
intracranial hemorrhage are low, but high morbidity and
mortality necessitate a careful consideration of management
risks and benefits. Current treatment approaches include
medical management, endovascular liquid embolization, fo-
cal radiosurgery, and surgical resection.
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Seminars in Neurology Vol. 33 No. 5/2013
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Q1: AU: The title in ref. 25 "Ogilvy, Stieg, Awad, et al, 2001" was updated, but differs from the author’s original: Stroke Council,
American Stroke Association. Recommendations for the management of intracranial arteriovenous malformations: A
statement for healthcare professionals from a special writing group of the stroke council, american stroke association.
Q2: AU: Medline reports the vernacular article title for ref. 67 "Castel, Kantor, 2001" is Morbidité et mortalité du traitement
chirurgical des malformations artérioveineuses cérébrales. Données actuelles et analyse de la littérature récente. (in
French).

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