PRIMER

Brain arteriovenous malformations

Michael T. Lawton1, W. Caleb Rutledge1, Helen Kim2, Christian Stapf3,
Kevin J. Whitehead4, Dean Y. Li4, Timo Krings5, Karel terBrugge5, Douglas Kondziolka6,
Michael K. Morgan7, Karam Moon8 and Robert F. Spetzler8
Abstract | An arteriovenous malformation is a tangle of dysplastic vessels (nidus) fed by arteries and drained
by veins without intervening capillaries, forming a high-flow, low-resistance shunt between the arterial and
venous systems. Arteriovenous malformations in the brain have a low estimated prevalence but are an
important cause of intracerebral haemorrhage in young adults. For previously unruptured malformations,
bleeding rates are approximately 1% per year. Once ruptured, the subsequent risk increases fivefold,
depending on associated aneurysms, deep locations, deep drainage and increasing age. Recent findings
from novel animal models and genetic studies suggest that arteriovenous malformations, which were long
considered congenital, arise from aberrant vasculogenesis, genetic mutations and/or angiogenesis after
injury. The phenotypical characteristics of arteriovenous malformations differ among age groups, with
fistulous lesions in children and nidal lesions in adults. Diagnosis mainly involves imaging techniques,
including CT, MRI and angiography. Management includes observation, microsurgical resection,
endovascular embolization and stereotactic radiosurgery, alone or in any combination. There is little
consensus on how to manage patients with unruptured malformations; recent studies have shown that
patients managed medically fared better than those with intervention at short-term follow‑up. By contrast,
interventional treatment is preferred following a ruptured malformation to prevent rehaemorrhage.
Management continues to evolve as new mechanistic discoveries and reliable animal models raise the
possibility of developing drugs that might prevent the formation of arteriovenous malformations, induce
obliteration and/or stabilize vessels to reduce rupture risk. For an illustrated summary of this Primer, visit:
http://go.nature.com/TMoAdn

The four major types of vascular malformations include
venous malformations, cavernous malformations,
telangi­ectases and arteriovenous malformations. An
arterio­venous malformation is a tangle of dysplastic ves-
sels comprising a nidus fed by arteries, drained by veins
and without intervening capillaries, forming a high-
flow, low-resistance conduit that shunts blood from the
arterial to the venous system (FIG. 1). They are the most
spectacular type of vascular malformation, with dilated
arteries converging from all directions and engorged
veins twisting and throbbing from the turbulence of
shunted blood flow. This Primer will focus only on
Correspondence to M.T.L.
brain arteriovenous malformations but will not address
e-mail: michael.lawton@
ucsf.edu
dural arteriovenous fistulas, cavernous malformations or
Department of Neurological other vascular malformations in the brain.
Surgery, University of Arteriovenous malformations are highly varied in
California, 505 Parnassus size, shape and location, making each malformation dif-
Avenue, M780,
San Francisco,
ferent, but patterns emerge and recognizable subtypes
California 94143, USA. with definable anatomy appear that enable a certain
degree of classification. In addition, their character­
Article number: 15008
doi:10.1038/nrdp.2015.8
istics vary with patients’ age, and so do the imaging and
Published online treatment options. In addition to conservative observa-
28 May 2015 tion, management includes microsurgery, embolization
and/or stereotactic radiosurgery, alone or in any combi-
nation. Microsurgery aims to produce curative resection,
with transarterial embolization used as a preoperative
adjunct. Stereotactic radiosurgery delivers radiation that
leads to obliteration of the arteriovenous malformation
over a 2–3 year latency period. Diagnosis mainly involves
medical imaging such as CT, MRI and angiography.
Epidemiology
On the basis of large-scale imaging data from seemingly
healthy volunteers, one brain arteriovenous malforma-
tion is found in every 2,000 MRI scans, which adds up
to an estimated prevalence of approximately 50 cases
per 100,000 (95% confidence interval (CI) 10–100)1.
The crude annual detection rate or incidence is esti-
mated at 1.3 per 100,000 patient years with relatively
stable detection rates across populations. Improved
access to diagnostic MRI might explain the increasing
detection rates of unruptured arteriovenous malforma-
tions, whereas the incidence of ruptured arterio­venous
malformations seems remarkably stable over time2–5
(TABLE 1). Arteriovenous malformations in the brain
are usually found in young adults between the ages of

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PRIMER

Author addresses
1
Department of Neurological Surgery, University of California, 505 Parnassus Avenue,
M780, San Francisco, California 94143, USA.
2
Department of Anesthesia and Perioperative Care, University of California,
San Francisco, USA.
3
Department of Neurology, APHP Hôpital Lariboisière, Paris, France, and DHU Neurovasc,
Université Paris Diderot, Paris, France.
4
Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA.
5
Department of Medical Imaging, University of Toronto, Ontario, Canada.
6
Neurological Surgery, University of Pittsburgh, Pennsylvania, USA.
7
Clinical Medicine, Macquarie University, Sydney, Australia.
8
Division of Neurological Surgery, Barrow Neurological Institute, Phoenix, Arizona, USA.
20 and 40 years6. Approximately half of patients present
with intracranial haemorrhage; the remaining patients
have focal or generalized seizures (20–25%), headaches,
focal neurological deficits or no symptoms (15%)7–11.
For previously unruptured arteriovenous malforma-
tions, the rate of haemorrhage is low (approximately 1%
per year) but increases fivefold once ruptured12–15 (TABLE 1).
Additional risk factors for future bleeding include increas-
ing patient age, Hispanic ethnicity, exclusively deep
venous drainage, deep location and radiological evidence
of previous haemorrhage. By contrast, the independent
effects of the nidus size, infratentorial location, associ-
ated unruptured aneurysms and venous dilatations have
not been confirmed in a prospective follow‑up study of
untreated patients12,16–18. Women do not show higher rup-
ture rates during pregnancy and puerperium, although
reports in the literature differ on this issue. In addition,
very low prevalence of brain arterio­venous malforma-
tions within families justifies that systematic s­creening of
first‑degree family members is not needed19,20.
Overall, the clinical consequences of a rupture of an
arterio­venous malformation in the brain are more benign
than intracranial haemorrhage attributed to other causes.
However, patients with a prior rupture show increased
long-term mortality rates compared with healthy con-
trols if left untreated21,22. A drawback for preventive inter-
ventions for unruptured arteriovenous malformations
is that these tend to be associated with a higher risk
of stroke and neurological deficits during short-term
(3 years) follow‑up13,23,24. For patients with arteriovenous
malformation-­associated epilepsy, population-based
data do not confirm a long-term benefit of arteriovenous
m­alformation eradication on future seizure occurrence25.
Mechanisms/pathophysiology
The pathogenesis of brain arteriovenous malformations
remains unclear. They have long been considered con-
genital, despite a lack of supporting evidence. Possible
causes might be miscues or miscommunications dur-
ing embryogenesis at the time that arteries and veins are
in direct contact without intervening capillaries. If this
pheno­menon persists after birth, instead of maturing into
a normal vascular architecture, arteriovenous malforma-
tions arise. They might also develop as a result of under-
lying genetic abnormalities that produce signalling errors
and structural defects. Another possibility is that arterio-
venous malformations are not congenital but acquired
after an injury, similar to dural arteriovenous fistulas26.
Artery and vein formation
To support the increased metabolic demands of a large,
active organism, vertebrates evolved a closed circulatory
system. Blood vessels emerged as distinct anatomical
conduits to transport nutrients to (arteries) and remove
waste from (veins) tissues. Arteries are thick-walled ves-
sels that are built to withstand the high-pressure flow
needed to supply target tissues. By contrast, veins are
larger, thin-walled, low-pressure vessels that convey
blood back to the heart, aided by valves that establish
directional flow and that combat gravity. Arteries and
veins often follow a parallel and counter-current course
but do not communicate directly. In fact, they are separ­
ated by capillary networks in target tissues, and speci­
fic control systems exist to prevent the formation of
prema­ture arteriovenous connections during develop-
ment and to maintain homeostasis of the vasculature
(FIG. 1). Arteriovenous malformations probably occur as
a c­onsequence of a failure in this control system.

a Normal b AVM
Rupture with local
damage and
Steal haemorrhage
phemonema
Arteries Veins

Capillary network Low resistance = High flow

Figure 1 | Schematic representation of normal vasculature and an arteriovenous malformation. 

Nature Reviews |aDisease
| In normal
Primers
circumstances, arteries and veins maintain strict distinctions and communicate only at the capillary bed.
b | Arteriovenous malformations (AVMs) are the result of direct connections between high-flow arterial vessels and
low-resistance venous capacitance vessels. Clinical consequences result from the direct and indirect effects of flow
disturbances and rupture-associated haemorrhage. Blood flow around an AVM prefers the low-resistance shunt
through the malformation over the surrounding capillary networks, thereby ‘stealing’ blood flow from adjacent brain
(the steal phenomenon).

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Table 1 | Detection and spontaneous rupture rates of brain AVMs in untreated patients
Detection rates Spontaneous rupture rates
Number per 100,000 per year (95% CI) Observed crude annual percentages (95% CI)
Study Ruptured Unruptured Total Ruptured Unruptured Total
Prospective population-based data sets
New York Islands 0.51 0.83 1.34 NA NA NA
AVM Study2 (0.41–0.61) (0.77–0.88) (1.18–1.49)
NOMASS3 0.55 NA NA NA NA NA
(0.11–1.61)
SIVMS4 0.51 0.61 1.12 NA NA NA
(0.37–0.69) (0.52–0.68) (0.90–1.37)
Retrospective population-based data sets
KPNC5 0.70 0.72 1.42 3.3% 0.7% 4.0%
(0.60–0.80) (0.63–0.83) (1.29–1.57) (2.9–3.6) (0.4–1.0) (3.8–4.2)
Finland15 NA NA NA 2.8 1.6 2.4
(2.4–3.2) (1.1–2.0) (1.9–2.8)
Patient-level meta-analysis, randomized data
MARS12 NA NA NA 4.8% 1.3% 2.3%
(3.9–5.9) (1.0–1.7) (2.0–2.7)
ARUBA13 NA NA NA NA 2.2% NA
(0.9–4.5)
ARUBA, A Randomized Trial for Unruptured Brain AVMs; AVM, arteriovenous malformation; KPNC, Kaiser Permanente of Northern
California; MARS, Multicenter AVM Research Study; NA, not analysed; NOMASS, Northern Manhattan Stroke Study; SIVMS,
Scottish Intracranial Vascular Malformation Study.

The circulatory system develops through the dif-
ferentiation of pluripotent angioblasts into endocardial
and endothelial cells in a process called vasculogenesis27.
The network of interconnected endothelial cells forms a
lumen and communicates with paired heart tubes, which
are lined by endocardial cells and are equipped to pres-
surize the system with rhythmic contraction. Primitive
vascular beds are converted into arteries, capillaries and
veins through a remodelling process (angiogenesis)
in response to molecular signals (angiogenic factors).
Angiogenic factors regulate the proliferation, migra-
tion and organization of endothelial cells, as well as the
growth and maturation of vessels. Different angiogenic
factors, as well as different expression levels of various
factors, ensure a distinct arterial or venous identity. Even
when the morphology of arteries and veins seem to be
similar early on in development, distinct genetic and
molecular differences are present28,29.
Vascular endothelial growth factor (VEGF) is an
important regulator of angiogenesis and vasculo­genesis
(FIG.  2a). Its activity is mediated by VEGF receptors
(VEGFR1 and VEGFR2) and modulated by a series of
additional co‑receptors27,28,30. The VEGF co‑receptor
neuro­pilin 1 (NRP1) is expressed on arterial endo­
thelial cells and regulates arterial differentiation31,32.
Ephrin B2 and Notch family members are also expressed
by the arteri­al endothelium. Notch signalling, which is
important for maintaining arterial identity 33, is activated
by sonic hedgehog (SHH)-stimulated expression of
VEGF34. Forkhead transcription factors such as FOXC1
and FOXC2 interact with the Notch signalling pathway
to regulate Notch target gene expression35. Similar to
arterial endothelial cells, venous endothelial cells have a
distinctive molecular profile. Venous endothelial cell fate
was once thought to be the default pathway that occurred
when arterial specification factors were absent. However,
development of the venous phenotype now seems to be
influenced directly by the retinoic acid-activated receptor
COUP-transcription factor 2 (COUP‑TF2)36. Expression
of COUP‑TF2 suppresses the expression of artery-­
specific genes and promotes expression of the venous
marker EPH receptor B4 (EPHB4)37.
Arteriovenous malformation syndromes
Most arteriovenous malformations are observed as
s­ingle, isolated or sporadic lesions in individuals, with-
out a clear genetic basis. The cause for the failure of
arterio­venous separation in these sporadic events is
unclear. Occasionally, multiple lesions in individuals
with genetic arteriovenous malformation syndromes are
observed, which has provided insight into some of the
crucial signal­ling pathways that govern arteriovenous
patterning (FIG. 2b).
Hereditary haemorrhagic telangiectasia, also referred
to as Osler–Weber–Rendu syndrome, is an autosomal
dominant disorder characterized by microscopic vascu-
lar malformations (known as telangiectases) at muco­
cutaneous surfaces and by macroscopic arteriovenous
malformations in internal organs, predominantly the liver,
lungs and brain38. Hereditary haemorrhagic telangiectasia
most commonly presents as epistaxis (nose bleed) owing
to ruptured telangiectases of the nasal mucosa, but bleed-
ing in the brain also occurs and is an important cause of
premature morbidity and mortality. This genetic condi-
tion revealed new genetic pathways governing arterio-
venous distinction. The causative genes in this condition

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are members of the transforming growth factor‑β (TGFβ) that interacts with endoglin on the endothelial cell sur-
family. For example, endoglin is a TGFβ co-receptor with- face to bind ligands and to stimulate kinase activity 41.
out a clear signalling function, and mutations in the gene Ligand binding results in the activation of SMAD pro-
encoding endoglin (ENG) causes hereditary haemor­ teins in the cytoplasm that ultimately leads to nuclear
rhagic telangiectasia type 1 (REF. 39). Mutations in the translocation and activation of SMAD4. Mutations in
gene encoding activin receptor-­like kinase 1 (ALK1; also SMAD4 result in a combined syndrome of hereditary
known as ACVRL1) cause type 2 hereditary haemor- haemorrhagic telangiectasia with juvenile polyposis42.
rhagic telangiectasia40. ALK1 is a type 1 TGFβ receptor Bone morphogenetic proteins (BMP9 and BMP10) bind
ALK1 with high affinity and induce downstream SMAD
a signalling 43. The above-­normal serum concentrations
SHH of BMP9 observed in patients with hereditary haemor-
rhagic telangiectasia suggest that BMP9 is involved in
VEGF
angiogenesis, although it is not otherwise considered as
a participant in this process44. Recent studies have shown
NRP1 that patients with an overlap syndrome characterized
by arteriovenous malformations and telangiectases har-
VEGFR EPHB4 EPHB2 boured mutations in BMP9, which further implicates this
EPHB2 factor in the formation of arteriovenous malformations45.
MAPK HEY COUP-TF2 Clinical improvements in symptoms have been observed
EPHB4
in patients with hereditary haemorrhagic telangiectasia
ERK Notch PI3K/AKT Notch treated with VEGF signalling inhibitors46,47.
pathway pathway Both endoglin and ALK1 are essential for vascular
development. Systemic inactivation of Eng and Alk1 in
FOXC1/2? MAPK
mice results in arteriovenous malformations and embry-
onic lethality 48,49. Regional or tissue-specific conditional
gene deletion of either Eng or Alk1 only produced arterio­
Arterial endothelium Venous endothelium
venous malformations when de novo angio­genesis was
stimulated by VEGF in mice50,51 (FIG. 3a). This finding is
b BMP9* consistent with observations in patients with hereditary
ALK1* haemorrhagic telangiectasia: the tissues most prone to
ENG*
1 2 3 developing telangiectases are those subjected to repeti-
TGFβ tive injury, damage and repair, such as the face, lips and
EPHB4
receptor fingers. This ‘response-to-injury’ hypothesis suggests that
the arteriovenous malformations phenotype includes an
? Gα Gβγ active angiogenic and inflammatory component in addi-
SMAD1/5/8 GNAQ* GDP tion to a genetic predisposition, typically an inherited
RASA1* allele loss of the responsible gene (ENG or ALK1) plus a
SMAD4* GTP later loss of heterozygosity (FIG. 3b).
Nucleus
The capillary malformation–arteriovenous malfor-
GTP GDP
Ras mation syndrome is another genetic syndrome result-
MAPK
ing in cerebral arteriovenous malformations and is
caused by mutations in RASA1 (REF. 52). The ensuing
Nature Reviews
Figure 2 | Molecular mechanism of artery and vein differentiation | Disease Primers
in homeostasis Ras GTPase protein inactivates Ras by hydrolysing GTP
and pathology.  a | Several mechanisms have been shown to define the separate arterial to GDP; loss of RASA1 activity, therefore, results in the
and venous phenotypes. Arteries express ephrin receptor B2 (EPHB2), whereas venous excessive activation of Ras and downstream pathways
endothelium expresses its ligand EPHB4. The arterial programme is maintained by
(FIG. 2b). Mechanistically, RASA1 might function down-
activation of the vascular endothelial growth factor (VEGF), neuropilin 1 (NRP1) and the
Notch pathway. Venous endothelial cells that lack NRP1 respond to VEGF with a different stream from EPHB4 in arteriovenous patterning to cause
programme that suppresses Notch signalling and favours EPHB4 expression. The arterio­venous malformation53. Vascular phenotypes in
transcription factor COUP‑TF2 that is expressed in venous endothelial cells suppresses zebrafish morphants were enhanced in the setting of
the arterial programme and favours venous markers. b | Molecular pathways involved in increased mTOR complex 1 (mTORC1) activity, which
arteriovenous malformation syndromes are depicted. (1) Hereditary haemorrhagic might indicate that mTOR inhibition may be a therapeu-
telangiectasia is a syndrome that results from impaired transforming growth factor-β tic approach for capillary malformation–arteriovenous
(TGFβ) signalling. Mutations have been observed in many members of this pathway, malformation syndrome53.
including the ligand bone morphogenetic protein 9 (BMP9), the TGFβ co‑receptors In addition, somatic mutations in GNAQ were found
activin receptor-like kinase 1 (ALK1) and endoglin (ENG), and SMAD signalling molecules. in the vascular malformations taken from patients with
(2) Capillary malformation–arteriovenous malformation syndrome is also associated with
Sturge–Weber syndrome, a condition characterized
arteriovenous malformations. Increased RAS activity due to missense mutations in
RASA1, which encodes a GTPase that might function downstream of EPHB4, are probably by port wine stains on the face and underlying lepto­
involved. (3) Malformations associated with Sturge–Weber syndrome result from meningeal angiomatosis54. GNAQ is a G protein α‑subunit
mutations in GNAQ that lead to increased G protein signalling. Vascular malformations involved in mediating signalling from G protein-­coupled
have been observed in patients with mutations in each of the genes encoding proteins receptors; mutations in GNAQ decrease GTPase activity
with an asterisk. FOXC, Forkhead box protein C; SHH, Sonic hedgehog. and increase signalling of associated G proteins, leading

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a been reported between brain arteriovenous malformations
b or response to injury 71–73. Predictors of disease course and
Homozygous loss of function Angiogenesis
(response to injury)
Somatic endothelial cell Bone-marrow-derived cell
Initation of AVM
Inflammation Haemodynamic changes
AVM progression
Figure 3 | Hypotheses of arteriovenous malformationNature pathogenesis
Reviews and the role
| Disease Primers
of ALK1.  a | Images of the brain of a mouse model of brain arteriovenous malformations
(AVMs) are shown. The mouse model was generated using regional conditional gene
deletion of activin receptor-like kinase 1 (Alk1) combined with stimulation of
angiogenesis via stereotactical injected adeno-associated viral vectors expressing
vascular endothelial growth factor (VEGF). Alk1 was conditionally deleted in the basal
ganglia of the brain by stereotactically delivering adenoviral vector with the gene
expressing Cre recombinase to transgenic mice with Alk1 flanked by loxP sites. Vessel
casting shows AVMs in the injected region of the brain of Alk1‑deficient mice (left panel,
arrow) with tangled dilated vessels (right panel). b | Hypotheses for AVM pathogenesis
and progression are summarized. Part a adapted with permission from REF. 200, Wiley.
to increased MAPK activity 54 (FIG. 2b). MAPK expression
is suppressed by the PI3K–AKT pathway to promote
the venous cell fate, suggesting that this is a possible
m­echanism for arteriovenous malformations55.
Genetic factors
Inspired by the genetic component of these specific
arterio­venous malformation syndromes, candidate-gene
and genome-wide association studies (GWASs) have
been performed to investigate genetic influences on the
more common, sporadically occurring arteriovenous
malformations. A common non-coding polymorphism
in ALK1 (ALK1 IVS3‑35A>G) was associated with spora­
dic brain arteriovenous malformations in two independ-
ent cohorts56–58. Polymorphisms in ENG56, integr­in β8
(ITGB8) 59, interleukin‑1β (IL1B) 60, angio­p oietin-
like 4 (ANGPTL4)61, G protein-coupled receptor 124
(GPR124)62, VEGF63 and matrix metallopeptidase  3
(MMP3)64 have also been found to be associated with
this condition. These associations have not yet been repli­
cated65, and none of the genetic variants linked to the
known familial syndromes has shown strong associations
with sporadic arteriovenous malformations in the brain,
except for the ALK1 variant66. However, an association has
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PRIMER
and genetic variations at chromosome 9p21 (REF. 67), a
genomic locus that is associ­ated with various cardio-
vascular phenotypes, including aortic and intra­cranial
aneurysms68,69, which might explain the link between
arteriovenous m­alformations and aneurysms70.
Whether genetic risk factors render individuals more
susceptible to developing arteriovenous malformations
remains to be determined. However, it is well established
that genetic modifiers can influence disease severity, clini­
cal course or response to treatment by modulating bio-
logical mechanisms such as inflammation, angiogenesis
response to therapy would have clinical use, and the need
for biomarkers of haemorrhage risk in both unruptured
and/or untreatable brain arteriovenous malformations is
particularly urgent. Candidate gene studies of sporadic
brain arteriovenous malformations have reported com-
mon polymorphisms in interleukin‑6 (IL6)74, IL1B60 and
EPHB4 (REF. 75), which are associated with increased
haemorrhagic risk. The apolipo­protein  E (APOE)
ε2 allele76 and the TNFA‑238G>A allele77 were associ-
ated with increased risk of recurrent rupture, in both
untreated78 and treated79 patients. Finally, the Val66Met
variant of brain-derived neurotrophic factor (BDNF),
which has been implicated in cerebrovascular disease
outcomes, has also been shown to influence the out-
comes after resection surgery 80–82. More specifically, this
variant was associated with worse functional outcomes
after resection in patients with unruptured arterio­venous
malformations83. Several lines of evidence, including
genetic, tissue and imaging studies of arteriovenous
malformations in patients and animal models, argue that
inflammation participates in the patho­physiology and
clinical course of this condition, possibly in the context
of response-to‑injury mechanisms.
Some of the reported associations are with single-
nucleotide polymorphisms (SNPs) that tag a particular
group of genetic variants in the genome (haplotype-
tagging variants). Although the molecular function of
most these SNPs remains to be determined, such mark-
ers can still be used as risk predictors. Additional studies
are needed to replicate these associations and identify
the functional relevance of these findings in independ-
ent cohorts. The future goal of clinical management of
brain arteriovenous malformations is to develop a pre-
diction score for specific clinical courses and therapeutic
outcomes that will incorporate genotypes of common
polymorphisms alongside epidemiological and morpho-
logical risk factors (including type of presentation, size,
location, age, sex and ethnicity). The advent of personal
genome sequencing will increase the future availability of
genotype information for screening and risk assessment.
Pathophysiology
In addition to the consequences of a rupture of the arterio­
venous malformation, the presence of an arterio­venous
malformation alone can affect the surrounding brain
tissue. Perilesional hypoperfusion can, over a period of
time, lead to the dilation of the perinidal capillary net-
work and the recruitment of leptomeningeal collaterals.
PRIMER
a Ultrasonography b MRI
AVM
c Before embolization d During and after embolization
PICA
feeder
AVM PICA Convexity
AVM
AVM Occluded
AVM
Figure 4 | Prenatal and postnatal diagnosis of an intracranial pial arteriovenous
Nature Reviews | Disease Primers
fistula.  Fetus with a fistulous pial arteriovenous malformation in the brain, diagnosed
in utero by the presence of a high-flow shunt on colour-Doppler ultrasonography, is
shown (part a). The infant presented at birth with severe heart failure. MRI scans show a
large posterior fossa arteriovenous malformation (AVM; part b, left image) as well as a
smaller sized convexity AVM associated with brain volume loss (part b, right image).
Digital subtraction angiography shows the left vertebral artery before embolization.
The posterior fossa AVM is a single artery-to‑vein fistula fed by the posterior inferior
cerebellar artery (PICA; part c). The image on the left shows the venous phase, whereas
the image on the right shows the arterial phase. After selectively catheterizing the
feeding PICA vessel (part d; left image) and embolizing it with coils (part d; right image),
the posterior fossa AVM was occluded and the distal basilar circulation was visualized.
Notably, the convexity AVM (part d; right image) was filling through the posterior
communicating arteries, which are also seen on this angiogram.
The formation of these new blood vessels (in a process
termed peri­nidal angiogenesis) results in a separate net-
work that is different from the true arteriovenous mal-
formation nidus84. Similarly, in superficially located
malformations, hypoxia can elicit angiogenesis using the
dural arteries as a source; thus, a complete arteriovenous
malformation obliteration must include closure of con-
tributing arteries from the external carotid system. The
surrounding brain tissue might also be affected by venous
congestion owing to high input of blood or reduced out-
flow (secondary to stenosis of the draining veins). This
pathology can be associated with cognitive decline, epi-
lepsy and neurological deficit85. A long pial course of the
draining vein might indicate that normal venous drainage
is restricted over a large cortical area, which increases the
risk of developing seizures85. Conversely, a short vein that
drains directly into a dural sinus is unlikely to interfere
with the normal regional drainage and cause seizures, but
it could result in hydrocephalus and cognitive decline from
global venous hypertension and decreased absorption of
cerebrospinal fluid86. Patients with venous congestion
might also demonstrate a pseudophlebitic pattern on digi-
tal subtraction angiography with an increased number and
calibre of corkscrew-like draining veins remote from the
arteriovenous malformations. The interaction between
the malformations and the brain is not static but can
change over time in a host- and time-dependent manner85.
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Cerebral proliferative angiopathy is an extreme
pheno­typic variant of classical arteriovenous malforma-
tions. Cerebral proliferative angiopathy occurs in young
adult women and is characterized by seizures. On MRI,
these patients have abnormal vascularity intertwined
with normal brain tissue. There is a discrepancy between
the nidus, which is often diffuse and large in size, and the
relatively normal size of feeding arteries and draining
veins, with only slightly increased transit times. The pres-
ence of gliosis suggests ischaemia in the adjacent brain
tissue, which in turn might induce sprouting angiogenesis
and the recruitment of dural arterial supply to the region.
The natural course of cerebral proliferative angiopathy
seems to be benign compared with the typical arterio-
venous malformations, but the risk of bleeding increases
after the first rupture. It is important to recognize this
entity because any type of intervention, including surgery
and radiosurgery, will have increased risk of neurological
d­eficits owing to the intervening normal brain tissue87.
Diagnosis, screening and prevention
Age-dependent diagnosis
The phenotypical characteristics of brain arteriovenous
malformations differ among age groups and, con­
sequently, symptoms and diagnostic tools also vary with
age. In neonates and infants, brain arteriovenous mal-
formations are rare. Imaging in these patients invariably
shows evidence of arteriovenous fistulas, which are large
and demonstrate direct communications between arter-
ies and veins without an intervening vascular network
or nidus (FIG. 4). They can easily be detected by MRI
and magnetic resonance angiography (MRA), which
might also show brain volume loss in the parenchyma
adjacent to the lesion, which is an indication for urgent
treatment 88. CT and CT angiography are performed
when haemorrhage is suspected and the precise source
of bleeding is sought. Catheter angiography by means of
digital subtraction angiography is typically performed
at the time of endovascular treatment or in prepara-
tion for surgery. High-flow arteriovenous fistulas might
result in systemic symptoms, including congestive heart
failure, and neurological symptoms from arterial steal,
regional brain ischaemia, focal neurological deficits and
seizures. The presence of multiple arteriovenous fistulas
should raise the possibility of a hereditary haemorrhagic
telangiectasi­a disorder 89.
In children and young adults, true nidal arteriovenous
malformations with artery-to‑vein communications
through an abnormal vascular network occur in addi-
tion to the arteriovenous fistulas. Imaging with MRA, CT
angiography or digital subtraction angio­graphy shows
enlarged feeding arteries and draining veins, as well as
the intervening nidus.
In adults, nidal arteriovenous malformations are
observed almost exclusively. Diagnosis should include a
detailed analysis of both the nidus and the adjacent brain
parenchyma. CT angiography or digital subtraction
angiography are used to determine the point of rupture
in patients with bleeding, whereas MRI is the preferred
imaging modality for patients with non-haemorrhagic
symptoms. Digital subtraction angiography continues to

be the gold standard for the characterization of the feed-
ing arteries, nidus angioarchitecture and draining veins,
and is essential for accurate arteriovenous malformation
grading and treatment planning 90.
Imaging techniques
CT and related techniques. CT scans are performed in
patients with suspected intracranial bleeding; when
haemorrhage is confirmed, CT angiography is performed
to rapidly diagnose the underlying arteriovenous mal-
formations. This technique might also pinpoint the site
of bleeding from feeding artery aneurysms, intranidal
aneurysms or venous varices (FIG. 5). Modern CT scan-
ners can image brain perfusion and show three distinct
patterns of extranidal parenchymal perfusion abnormali-
ties91. The first is functional steal, which is a redirection
of the blood flow from surrounding brain tissue through
the arteriovenous malformation that disrupts the normal
functioning of the brain tissue. It shows on a CT scan as a
reduction in cerebral blood flow, cerebral blood volume
and mean transit time due to a sump effect from the artery
supplying the arteriovenous malformation. Patients with
this abnormality commonly present with seizures. The
second pattern is termed ischaemic steal and is character-
ized by decreased cerebral blood flow and cerebral blood
a b
* resonance veno­graphy depicts venous outlet obstruction,
c d
* of the superficial outlets with subsequent rerouting into
* the deep system, possibly suggesting a less stable lesion.
e f
Nature artery
Figure 5 | Imaging of a feeding | Disease Primers
Reviewspseudoaneurysm
with haemorrhage.  An axial CT scan shows
intraparenchymal and intraventricular haemorrhage
(marked by arrowheads; part a). Coronal CT
angiographical image shows the pseudoaneurysm
(part b). Digital subtraction angiography of the vertebral
artery shows diagnosis of pseudoaneurysm (asterisks),
seen in anterior-posterior (part c) and lateral (part d)
views; selective catheterization of the parent artery
(part e; arrow); and therapeutic embolization and
occlusion of the pseudoaneurysm, which protect against
future bleedings (part f).
NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 7
© 2015 Macmillan Publishers Limited. All rights reserved
PRIMER
volume with increased mean transit time in the brain
parenchyma owing to indirect collateral flow to the shunt
from adjacent arteries. These patients most commonly
present with a focal neurological deficit. The third abnor-
mality is venous congestion, which is characterized by
increased cerebral blood volume and mean transit time in
remote parts of the brain due to high-pressure flow in the
draining veins of the arteriovenous malformation. These
patients present with progressive neurological deficits.
MRI and related techniques. To screen or electively inves-
tigate the presence of arteriovenous malformations, MRI
is the imaging modality of choice because it depicts the
shunt and assesses perinidal brain parenchyma. MRA
shows varying degrees of dilatation of the arterial feed-
ers depending on the shunt volume. Flow-induced
aneurysms might occur along the feeding arteries. It is
important to look for signs of prior haemor­rhage, such
as signal de­phasing on gradient-recalled echo imaging
and perinidal gliosis characterized by an increased signal
on T2‑weighted and fluid-attenuated inversion recovery
imaging. Most arteriovenous malformations have minimal
or no mass effect, unless there are large venous pouches
that compress adjacent brain parenchyma and cerebro­
spinal fluid drainage pathways. In patients with symptoms
other than haemorrhage, the presence of perinidal brain
oedema is an important finding that is often associated
with partial venous outlet thrombosis causing progressive
neurological deficits, headaches and/or seizures. Magnetic
venous ectasia and sinus thrombosis. A long pial course of
a draining vein is associated with a higher incidence
of chronic venous ischaemia and seizures90. The absence of
cortical venous drainage in a superficially located brain
arteriovenous malformation might indicate thrombosis
Patients with longstanding venous hyper­tension might
show bilateral, symmetric parenchymal calcifications
within the basal ganglia and subcortical white matter
owing to chronic venous ischaemia.
Angiography. Angiographic analysis of arteriovenous
malformation architecture specifically addresses
the nature and number of the feeding arteries, as well
as the presence of flow-related aneurysms. In addition,
angio­graphy can reveal the number of separate compart-
ments within the malformation, any intranidal or peri­
nidal a­rterial a­neurysms, and the nature of the venous
drainage, as well as associated varices and stenoses. All
of these elements are best assessed by digital subtraction
angio­graphy. The two basic types of feeding arteries are
direct arterial feeders, which end in the arteriovenous
malformation, and indirect arterial feeders, which supply
the arteriovenous malformation via small branches that
arise from the involved artery but also continue ‘en pas-
sage’ to normal brain tissue distal to the malformation.
Direct feeders might be large cortical arteries or smaller
perforators coursing through white matter or ventri-
cles. Flow-related aneurysms along the feeding arteries
are caused by increased shear stress and can indicate
PRIMER
Table 2 | Grading systems for brain arteriovenous malformations*
Variables Parameters Points
Spetzler–Martin grading (total score = 5)
Size <3 cm
3–6 cm
>6 cm
Venous Superficial drainage in cortical veins and convexity sinuses
drainage
Deep drainage in the vein of Galen
Eloquence No
Yes (located in sensorimotor cortex, language areas,
visual cortex, hypothalamus, internal capsule, brain stem,
cerebellar peduncle or deep cerebellar nuclei)
Lawton–Young grading (total score = 5)
Age <20 years
20–40 years
>40 years
Bleeding Yes
No
Compactness Yes
No
*Table reproduced from Kim, H. et al. Validation of the supplemented Spetzler–Martin grading
system for brain arteriovenous malformations in a multicenter cohort of 1009 surgical patients.
Neurosurgery 76, 25–33 (2015), with permission from Wolters Kluwer Health.
increased vascular fragility and haemorrhage risk. The
aneurysms might resolve following curative treatment
of the arteriovenous malformation92. Intranidal arterial
aneurysms (FIG. 5) represent an angioarchitectural weak
point and are often pseudoaneurysms without a wall and
project into a haematoma. They are usually small (<3 mm)
and can be treated by embolization93. The arterio­venous
malformation nidus can have both fistulous and glomeru­
lar compartments, the former being high-flow shunts
amenable to endovascular therapy and the latter being
an intervening network of pathological vessels that might
not be as easy to treat by embolization. Evaluation of the
venous portion of the arteriovenous malformation should
consider the anatomy of drainage (superficial, deep or
mixed) and characteristics of the venous outflow, such as
focal stenosis, venous pouches and associated sinus steno­
sis or occlusion. Drainage into the deep venous system
carries a high risk of haemorrhage and indicates deep
location that might make surgery difficult.
Screening and monitoring
Evidence supporting the use of imaging to screen and
monitor patients with brain arteriovenous malforma-
tions is lacking, even for relatives of patients with spora­
dic arteriovenous malformations. Screening of patients
and family members suspected of hereditary haemor-
rhagic telangiectasia is performed differently in different
c­ountries, with many North American centres recom-
mending screening with MRI in infancy to be followed by
repeated MRIs at 5‑year intervals at least until the age of
8 | 2015 | VOLUME 1 www.nature.com/nrdp
© 2015 Macmillan Publishers Limited. All rights reserved
45 years. Surveillance MRI may be less frequent in other
countries. In patients with sporadic arteriovenous mal-
formations managed conservatively, MRI examinations
are recommended every 5 years until the age of 65 years
1
to detect silent haemorrhages, unless new symptoms
necessitate an earlier examination94. CT angio­graphy
2 and digital subtraction angiography have no role in the
3 r­outine follow‑up care of patients who are clinically
stable. Follow‑up imaging after treatment of a sporadic
0
arteriovenous malformation is performed to confirm
1 complete obliteration and is essential after embolization
0 and radiosurgery. This surveillance can also identify the
delayed impact of the treatment, which is particularly
1
important after radiosurgery. MRI is the optimal initial
method, but angiography is necessary to confirm com-
plete obliteration. Angiograms at 5‑year intervals are
also recommended in paediatric patients after complete
1 resection of the malformation because of the reported
2 recurrence risks in this population.
3
Management
0 Grading and classification
1 Grading systems are an important method to describe
arteriovenous malformations. In their efforts to avoid
0 surgical complications and poor neurological out-
1 comes with microsurgical resection of brain arterio-
venous malformations, neurosurgeons have identified
factors that determine operative risks and developed
criteria that transform complex management decisions
into algor­ithms. These grading systems have become
more than predictors of surgical risks; they are short-
hand descriptions of the pathology itself and a part of
the language of brain arteriovenous malformations. The
Spetzler–Martin grading system is the predominant
classification scheme because it is simple, applicable at
the bedside and accurate. It uses size, eloquence (critical
function of surrounding brain parenchyma) and venous
drainage patterns95 (TABLE 2).
Not all factors important to surgical selection and
outcome are part of the Spetzler–Martin system. Age,
haemorrhagic presentation and compactness are also
critical. Compact arteriovenous malformations with
tightly woven arteries and veins have distinct borders
that separate cleanly from the adjacent brain tissue,
whereas diffuse malformations have ragged borders and
are intermixed with brain matter. The Lawton–Young
grading system incorporates these other factors (TABLE 2).
Points are assigned for the ABC’s of arteriovenous mal-
formations: age, bleeding and compactness. This grading
system supplements rather than replaces the traditional
Spetzler–Martin system. The sum of the Spetzler–
Martin and Lawton–Young grades, or the supplemented
Spetzler–Martin grade, provides clinicians with the
highest predictive accuracy of any grading system and
establishes boundaries for arteriovenous malformation
operability 96–98 (TABLE 3).
In addition, a new classification of arteriovenous mal-
formations has been proposed, whereby seven types have
been described depending on their location in the brain:
frontal, temporal and parieto-occipital lobes, ventricles,
deep central core, brainstem and cere­bellum99 (TABLE 4).
 PRIMER

Table 3 | Neurological outcomes by grade after microsurgical resection* Microsurgery. From a microsurgical perspective, every
arteriovenous malformation can be thoroughly deci-
Worse Improved or unchanged phered and methodically treated in eight steps: exposure,
Grade n Percentage n Percentage subarachnoid dissection, defining the draining vein,
Spetzler–Martin grade
defining the feeding arteries, pial dissection, parenchy-
mal dissection, ependymal or deep dissection, and finally
I 17 7 218 93 resection (FIG. 6). The surgery begins by a craniotomy to
II 80 21 295 79 expose the cortical surface on which the arteriovenous
malformation is based. Craniotomies are large and are
III 84 29 209 71
not considered minimally invasive because some periph-
IV 37 38 61 62 ery is needed to survey the course of feeding arteries and
V 4 50 4 50 draining veins as they travel to and from the arteriovenous
malformations. Furthermore, room is needed to dissect
Supplementary grade
the subarachnoid spaces and accommodate brain shifts.
I 5 6 84 94 Subarachnoid dissection involves surveying the arterio-
II 30 16 161 84 venous malformation under the microscope, and opening
the labyrinth of subarachnoid spaces, and deconstruct-
III 70 18 314 82 ing arachnoid membranes, disconnecting interlobular
IV 92 32 196 68 trabeculae and intercommunicating cisternal compart-
V 25 44 32 56
ments. Subarachnoid dissection is a translation of angio-
graphical anatomy onto the surgical field, and abnormal
Supplemented Spetzler–Martin grade feeding arteries and distorted draining veins are inspected
2 0 0 24 100 for clues to their angiographical identity.
The most important feature underlying successful
3 1 2 59 98
arteriovenous malformation surgery is that the draining
4 21 10 182 90 vein must be preserved until the very end of the resection.
5 54 19 237 81 Although placing efferent veins at the centre of dissection
strategy might seem counterintuitive in the presence of
6 56 24 176 76
ferocious arterial afferents, intra­operative ruptures occur
7 54 39 84 61 when outflow is obstructed, leading to increased intra-
8 30 63 18 38 nidal pressure and distension of the malformation, fol-
lowed by rupture and bleeding in the surgical field. No
9 6 55 5 45 predefined strategy to manage the bleeding for arterio­
10 0 0 2 100 venous malformation ruptures exists as for aneurysm
*Table reproduced from Kim, H. et al. Validation of the supplemented Spetzler–Martin grading rupture. Tamponade or holding pressure is ineffective for
system for brain arteriovenous malformations in a multicenter cohort of 1009 surgical patients. managing bleeding because there are multiple bleeding
Neurosurgery 76, 25–33 (2015), with permission from Wolters Kluwer Health. sites, suction might not clear the field and afferent arter-
ies are too numerous to control quickly or completely.
Preservation of the efferent vein is, therefore, of utmost
Within each type, the brain surface on which the arterio­ importance during surgery. In addition, the vein guides
venous malformation is based (for example, lateral, the dissection to the nidus. Indeed, one-third of malfor-
medial or basal) or other specific anatomical regions mations are beneath the cortical surface and two-thirds
(such as midbrain, pons and medulla) further categor­ have superficial venous drainage, which means that many
ize them in 4–6 subtypes. Using this classification, the only have an arterialized vein on the surface. Draining
range of brain arteriovenous malformations is simplified veins also visually illustrate the progress of the resection
to a finite number of different subtypes, each character- as their colour changes from red to purple to blue as the
ized by its own arterial supply, draining veins, eloquent dissection proceeds.
structures, surgical approach and management strategy. Another important principle is that arteries are occlu­
Categorization helps to guide management, facilitate ded as close as possible to their point of contact with the
learning and sharpen the language of brain arteriovenous arteriovenous malformation. More proximal occlusion
malformations encountered in practice99. can sacrifice normal branches and might lead to infarcts
in the adjacent brain tissue. However, more distal occlu-
Treatment sion can elicit bleeding from the nidus or preserve proxi-
Patients with brain arteriovenous malformations are mal feeding branches. Several types of afferent arteries
managed by non-interventional follow‑up (conserva- are found proximal to the arteriovenous malformations:
tive management) or invasive treatment. Currently, no terminal or direct feeding artery; transit or indirect artery;
drugs are available to treat arteriovenous malforma- perforating artery; choroidal artery; and bystander artery
tions or to prevent haemorrhage, but the associated that does not supply the arteriovenous malformation. Each
seizures can be managed with anticonvulsant medica- arteriovenous malformation has its unique set of arterial
tions and recurrent headaches with preventive or acute feeders that determine its ‘fingerprint’; complete closure
symptomatic treatment. of these arterial feeders is central to successful treatment.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 9

© 2015 Macmillan Publishers Limited. All rights reserved

PRIMER

Dissection of the pia mater of the brain is directed involved brain tissue — must be respected by maintain-
at feeding arteries on the cortical surfaces, also called ing a close distance to the arteriovenous malfor­mation.
arterial fronts, where these superficial inputs intersect Parenchymal dissection detaches the arterio­venous
the arteriovenous malformations. During this surgi- malformation from the brain and comprises two-
cal step, eloquence — or functional importance of the thirds of the circumdissection. Every converging artery
supply­ing the arteriovenous malformation is closed and
second­ary draining veins are trimmed. Most arterio­
Table 4 | Classification and prevalence of brain AVMs* venous malformations are compact, have distinct
Type n Percentage‡ margins and are easily separated from adjacent brain
tissue, all of which facilitate parenchymal dissection.
Frontal AVMs §
A diffuse arterio­venous malformation, however, is
Lateral frontal 48 8 wound loosely, as if unravelled, with indistinct margins,
Medial frontal 21 4 intermixed brain and poor separability. They are diffi-
Paramedian frontal 24 4 cult to dissect and force the neurosurgeon to establish
Basal frontal 21 4 the plane of sepa­ration between the malformation and
brain. The interplay of eloquence and haemostasis pull
Sylvian frontal 21 4
in and push back the circumdissection, and challenge
Temporal AVMs|| the n­eurosurgeon to find the right dissection distance.
Lateral temporal 76 13 Finally, ependymal dissection takes place at the
Basal temporal 12 2 tip of the classical arteriovenous malformation cone,
which is tapered to the ependyma. Ependymal dissec-
Medial temporal 17 3
tion might be a confusing term because many arterio-
Sylvian temporal 7 1 venous malformations do not reach a ventricle, but it
Parieto-occipital AVMs ¶
describes the deep dissection that comes at the end of
Lateral parieto-occipital 52 9 the surgery. This dissection is diametrically opposed
Medial parieto-occipital 17 3 to the neurosurgeon and is inherently difficult to see
because it is physically blocked by the malformation
Paramedian parieto-occipital 29 5
nidus. This plane receives perforating and choroidal
Basal occipital 10 2 artery supply, which can be difficult to coagulate. The
(Peri)ventricular AVMs# arteriovenous malformation can be resected when the
Callosal 23 4 sides of the malformation have all been circumferen-
Ventricular body 5 1 tially dissected, the arterial supply is disconnected and
the draining vein turns blue. Expected outcomes after
Atrial 9 2
microsurgical resection in patients with favourable
Temporal horn 5 1 grades are generally excellent 95,100–109 (TABLE 5).
Deep AVMs**
Pure Sylvian 8 1 Embolization. Endovascular management of arterio­
Insular 25 4 venous malformations varies with a patient’s age. It has
a major role in the treatment of neonates and infants
Basal ganglial 10 2
with arteriovenous fistulas and major cardiac symptoms
Thalamic 13 2 or progressive brain ischaemia, who require immediate
Brainstem AVMs‡‡ intervention. The transarterial closure with polymeric
Anterior midbrain 1 0 glue is the most efficient method in this age group88. In
Posterior midbrain 6 1
addition, treatment at centres with experi­enced teams
and skilled experts equipped to handle the complexities
Anterior pontine 6 1
of care is highly recommended. In children and young
Lateral pontine 7 1 adults, endovascular management is typically performed
Anterior medullary 1 0 as an adjunct to microsurgery because these individuals
Lateral medullary 5 1 more frequently present with bleeding than older adults
and often require life-saving removal of the haematoma.
Cerebellar AVMs §§
Preoperative embolization aims to obliterate the bleeding
Suboccipital cerebellar 18 3 source, such as a pseudo­aneurysm, and/or to eliminate
Tentorial cerebellar 16 3 deep feeding arteries that might not be surgically accessi-
Vermian cerebellar 25 4 ble until late in the dissection. In a small and select group
Tonsillar cerebellar 7 1 of adults, embolization can be performed as a curative
intervention. However, curing brain arteriovenous mal-
Petrosal cerebellar 16 3
formations solely by endovascular means might only be
Mixed AVMs 39 7 possible in approximately 20% of malformations, particu-
*Types of brain arteriovenous malformations (AVMs) identified during surgery of 600 patients. larly those that are small, and have a single direct feeder
‡
Percentage of patients identified with a specific subtype. §23%. ||19%. ¶18%; #7%. **9%; ‡‡4%;
§§
14%. Table adapted from Table p.1 Lawton, Michael T.: Seven AVM’s Tenets and Techniques for and a single compartment110. Palliative embolization aims
Resection, with permission from Thieme Medical Publishers. to eliminate the largest fistulas in the malformations and

10 | 2015 | VOLUME 1 www.nature.com/nrdp

© 2015 Macmillan Publishers Limited. All rights reserved


a b
Draining vein
AVM
1 are considered to be unsafe because embolic material will
Feeding artery
c d
PreFrA PreFrA
Frontal
lobe 3 tion of glue into veins, which might subsequently lead
AVM AVM
PreCenA
Draining 2 arteriovenous malformations with multiple arterial feed-
Draining
vein PreCenA
vein
e f
Draining vein
AVM 4 first, even when embolization is the method of treatment.
AVM
PreCenA
Draining
PreFrA vein
Nature Reviews
Figure 6 | Resection strategy of arteriovenous malformations.  | Disease Primers
a | Angiogram
(carotid artery dye injection, lateral view) of an arteriovenous malformation (AVM;
supplemented Spetzler–Martin Grade 6) is shown. b | To conduct microsurgical
resection of the AVM, (1) an orbital-pterional craniotomy was performed (dashed line).
c | The surgeon sees the arterial inputs from the precentral artery (PreCenA) and the
prefrontal artery (PreFrA), both branches from the middle cerebral artery, the AVM and
the draining vein. d | A schematic representation of the photograph in part c is shown.
Surgery continues by identifying (2) the draining veins and (3) the cortical arterial
feeders. e | Schematic representation of the AVM in part c as seen in a coronal
cross-sectional slice through the frontal lobes is shown. Next, (4) the inferior front of
arteries near the middle frontal gyrus is interrupted, taking care to preserve en passage
flow in transit arteries. Finally, the frontal parenchyma is circumdissected, and the AVM
is mobilized to expose lenticulostriate artery feeders on the inferior side. f | After
complete circumdissection, the AVM darkened.
is performed in patients presenting with progressive
neurological deficits or seizures, and it can result in
s­tabilization or improvement of clinical symptoms.
The techniques and approaches used for emboli-
zation therapy are highly variable and include differ-
ent agents and devices, such as n‑butyl cyanoacrylate
(NBCA) glue, liquid embolic agents (such as Onyx,
Covidien, USA) and coils, and a variety of approaches
including transarterial, transvenous or combinations
thereof. The transarterial route is the most frequently
used approach and liquid glue is the classic embolic
agent. Onyx is a newer liquid agent with very different
properties; it has higher obliteration rates (40–80%) than
NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 11
© 2015 Macmillan Publishers Limited. All rights reserved
PRIMER
traditional glue (20–40%)111–113 but is also associated with
increased complication risks. Indeed, the rate of perma-
nent neuro­logical deficit and death is 8–15% with Onyx
versus 3–7% with glue114. Embolization with both types
of liquid embolic materials is safe through direct arterial
feeders, as long as the catheter tip is positioned beyond
an artery supplying normal brain tissue and potential
reflux of embolic material, which might block such arter-
ies, is avoided. Indirect or ‘en passage’ feeding arteries
migrate to distal arteries88. Arteriovenous fistulas and fis-
tulous communications in arteriovenous malformations
are best treated by transarterial injection of glue (FIG. 7).
A drawback of the use of glue is the potential propaga-
to secondary venous occlusion and increased haemor-
rhage risk. Coils might be safer to use in these fistulous
subtypes. In some cases, coils can also be used to reduce
flow before glue embolization. Small- and medium-sized
ers have an improved chance of cure with Onyx emboli-
zation, but with the understanding that such cure may be
associated with manifest complication risk.
When arteriovenous malformations are associated
with aneurysms, the symptomatic lesion is always treated
In an analysis of 662 patients with brain arterio­venous
malformations, 305 patients had associated aneu-
rysms, and the incidence of rebleeding was significantly
increased in those harbouring intranidal aneurysms
(P < 0.002)115. In another series of 678 patients with brain
arteriovenous malformations, the presence of associated
aneurysms raised the annual risk of future bleeding from
3.9% per year (without aneurysms) to 6.9% (with associ­
ated aneurysms) (P = 0.01)116. Thus, these associated
aneurysms require attention, and endovascular therapy
is considered when it lies beyond the surgical field. The
role of embolization therapy will continue to increase as
newer embolic agents and delivery systems are devel-
oped that have improved obliteration rates and fewer
a­ssociated complications.
Radiosurgery. Stereotactic radiosurgery involves the
precise, image-guided delivery of a radiation dose to a
defined target. The aim is to close the lumen of an involved
vessel and to obliterate the arteriovenous malformation.
Stereotactic radiosurgery has become an increasingly
attractive option for patients with arteriovenous malfor-
mations, as it can produce excellent results with a modest
risk117–124. The main risks of stereotactic radiosurgery are
twofold. First, a latency period exists before maximum
obliteration after the procedure, in which haemorrhage
risk remains and obliteration can typically take up to
4 years. Second, the process can affect or damage adja-
cent neural structures, leading to neurological morbidity.
These adverse radiation effects are typically inflamma-
tory but can also be haemo­dynamic125. Complete oblit-
eration rates vary between 50% and 90% depending on
the arteriovenous malformation volume117,119,126–130. Once
complete obliteration is confirmed by angiography, the
lesion can be considered cured with <1% remaining
PRIMER

Table 5 | Summary of microsurgical results in patients with low-grade arteriovenous malformations

Study Year n Morbidity (%) Mortality (%) Cure rate (%) Haemorrhage (%)
Spetzler, Martin 95
1986 44 2.3 0 NA NA
Heros103 1990 47 2.2 2.2 100 0
Sundt 109
1991 84 2.2 0 100 0
Sisti, Stein108 1993 67 1.5 0 94 0
Hamilton, Spetzler 101
1994 40 0.0 0 100 NA
Schaller, Schramm106 1997 50 3.2 0 98 2
Schaller, Schramm107 1998 81 0.0 0 NA NA
Harbaugh105 1998 26 3.8 0 100 0
Hartmann102 2000 48 6.6 0 NA NA
Morgan104 2004 220 0.9 0.5 100 0
Davidson, Morgan 100
2010 296 0.7 0 97 NA
Lawton110 2015 232 2.4 0.5 98 0
Total – 1,235 2.2 0.3 98.5 0.3
NA, not analysed.

risk of subsequent haemorrhage127. Successful oblitera-
tion after stereotactic radiosurgery depends directly on
the amount of radiation delivered and on the accurate
identifi­cation of the arteriovenous malformation shunt.
The morbidity of stereotactic radiosurgery is a function
of the radiation dose and the total volume treated. Blood
flow in the arteriovenous malformation might also cor-
relate with the obliterative response, but to date this has
been difficult to measure and study. As such, a balance
must be struck between maintaining efficacy of the
t­reatment and m­inimizing risk127,131–141.
Preclinical and human clinical data have been used
to create both dose–response and dose–complication
curves. The goal was to achieve a low permanent risk
of injury to the adjacent brain tissue. The lower doses
needed to achieve this risk inevitably lead to lower
obliteration rates, especially in large-volume arterio-
venous malformations. However, a number of new con-
cepts have been proposed to overcome the biological
drawbacks of low doses142,143, including staged volume
or staged dose approaches144–146. With volume-staged
radiosurgery, large malformations are divided into
smaller portions and treated separately with safe doses
in multiple sessions, as if each portion was an indivi­
dual malformation. With dose-staged radiosurgery, large
malformations are treated with hypofractionated stereo-
tactic radiosurgery or with repeat radiosurgery months
or years later if there is no evidence of obliteration.
Arteriovenous malformations targeting is dependent
on high-resolution imaging (FIG. 8). Typically, this includes
both stereotactic volumetric axial plane imaging (usually
MRI or CT) in conjunction with digital sub­traction angio­
graphy 147–151. The imaging is used to identify the nidus or
arteriovenous shunt. Quantification of blood flow might
assist nidus definition but this is not yet readily avail-
able. Once the target is defined, a margin dose is selected
(a range of 16–25 Gy in a single procedure is common;
obliteration rates seem to drop at doses below 16 Gy).
A margin isodose line of 50–80% is used with most
radiosurgical devices; a higher central dose might lead to
a better oblitera­tion response when using select­ive confor-
mal radiotherapy140,152. If post-­radiosurgery adverse effects
occur, several medical strategies can be used to treat the
effects. Such strategies include the use of corticosteroids,
vitamin E, pentoxi­fylline (a phosphodi­esterase inhibitor)
and bevacizumab153 (a VEGF i­nhibitor); a­nticoagulation
or h­yperbaric o­xygen are rarely used.
Complex and large arteriovenous malformations that
are not suitable for resection might be considered for
endo­vascular embolization followed by stereo­tactic radio­
surgery. The goal of embolization is to reduce the volume
of the malformation and to facilitate radio­surgery119,154–171.
However, sometimes embolization reduces the blood
flow rather than the volume, which might not facilitate
radiosurgery. Indeed, some authors report that emboli-
zation before stereotactic radiosurgery can lead to worse
overall outcomes. Multiple case series have shown that
stereo­tactic radiosurgery obliteration rates for patients
who receive prior embolization are significantly lower
than those who are not embolized112,129,161,172–179. This
finding might, however, be an artefact of patient selec-
tion. Some hypothesize that embolic agents can act as
radioprotectants, others hypothesize that embolization
promotes angiogenesis or that dose planning becomes
more difficult as the nidus becomes less well defined172,180.
Because of this evidence, one option would be to consider
embolization following radiosurgery. In addition, because
arteriovenous malformations might have associated
aneurysms that constitute an additional risk of haemor­
rhage, one should consider repairing the aneurysm by
microsurgical or endo­vascular means. However, a flow-
related a­neurysm might regress spontaneously follow-
ing closure of the arteriovenous malformation. Another
consideration is to resect part of the irradiated arterio-
venous malformation that did not completely obliterate
angiographically. Arteriovenous malformations that are
more amenable to resection have little vascularity and
are easily accessible.

12 | 2015 | VOLUME 1 www.nature.com/nrdp

© 2015 Macmillan Publishers Limited. All rights reserved


Multimodal approach. Treatment of arteriovenous mal-
formations often consists of a multimodal approach that
includes microsurgical resection, endovascular emboli-
zation and stereotactic radiosurgery, either alone or in
combination176. The aim is to target the vessels involved
in the arteriovenous malformation from all sides: resec-
tion on the outside, embolization on the inside and
radiosurgery to the vessel wall. A multi­disciplinary
team will determine which approach might be opti-
mal for a given patient. The primary goal of treatment
is complete arteriovenous malformations obliteration,
thereby completely eliminating any risk of rupture10. If
lesions are only partially treated, patients remain at risk.
That is, non-curative treatment of arterio­venous mal-
formations, independent of approach, exposes patients
to treatment risks but does not lower or eliminate the
haemorrhage risk22,116,181.
The development of management plans is chal-
lenging owing to the variety of ways that embolization,
microsurgery and radiosurgery can be used alone or in
combination. Typically, microsurgery is favoured as it
has superior cure rates and acceptable rates of associ-
ated morbidity and mortality. The Spetzler–Martin and
Lawton–Young grading systems provide rapid, bed-
side assessments, and a supplemented Spetzler–Martin
grade ≤6 points makes microsurgery a viable option98.
If patients would further benefit from embolization
and if the risk is acceptable, double modality therapy is
appropriate. If the risk of embolization is too high — for
example, due to a haematoma or elevated intracranial
pressure — only micro­surgery should be performed.
After microsurgical treatment, an angiography is per-
formed to determine the adequacy of resection. Only
complete angiographical obliteration is considered cura-
tive or protective against future haemorrhage22,116,181.
Before surgery 3 years after surgery Transarterial glue injection
a b c d
Anteroposterior view
Lateral view
Figure 7 | Arteriovenous malformation occlusion through Nature radiosurgery andPrimers
Reviews | Disease
transarterial glue embolization.  Carotid angiograms show a left parietal
arteriovenous malformation (AVM) fed mainly by one large middle cerebral artery feeder
(marked by arrows; part a). The patient was treated with Gamma Knife radiosurgery,
which failed to obliterate this fistulous AVM, seen on carotid angiograms 3 years later
(part b). The malformation was cured with transarterial glue injection, as seen on the skull
X‑rays showing the cast of glue (part c) and carotid angiograms with no further filling of
the malformation (part d).
NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 13
© 2015 Macmillan Publishers Limited. All rights reserved
PRIMER
Recurrence is rare, but young patients with deep venous
drainage are at increased risk182. Patients with residual
arteriovenous malformations undergo re‑operation for
complete resection if feasible and safe. Patients who
receive a deliberate incomplete resection are considered
for radiosurgery as part of triple modality therapy.
When patients are poor surgical candidates (supple-
mented Spetzler–Martin grade >6 points), radiosurgery
is performed. Small- and medium-sized arteriovenous
malformations are treated with conventional stereotactic
radiosurgery and large malformations are treated with
volume-staged radiosurgery, both without emboliza-
tion. Patients are monitored for 3 years and those with
incompletely obliterated arteriovenous malformations
are reconsidered for microsurgery 183. Criteria evalu-
ated in the arteriovenous malformations grading scale
might have changed in the meantime, particularly size,
haemorrhage status and diffuseness, which possibly
downgrades a malformation and renders a patient newly
eligible for microsurgery. In such cases, embolization is
considered as a preoperative adjunct.
In addition, many candidates for microsurgery can
also be candidates for radiosurgery, in which case radio-
surgery is considered a viable alternative. Analyses to
compare microsurgical and radiosurgical treatment
alternatives enable comparison of risks, advantages and
disadvantages, with particular emphasis on technical
differences, surgical morbidity, radiosurgical morbidity,
haemorrhage risk during the latency period and relative
efficacies of therapy.
Conservative observation involves close monitoring
of potential aneurysms on feeding arteries, both intra-
nidally and in the circle of Willis. Aneurysms ≥7 mm
in diameter that are associated with high-flow arterio-
venous malformations or with dysplastic morphology
need to be treated. Untreated aneurysms are monitored
with serial imaging and are only treated if they enlarge.
Evidence from clinical studies
Many studies have confirmed that microsurgery is
superi­or in treating low-grade arteriovenous malforma-
tions (Spetzler–Martin grade I and II) compared with no
treatment, embolization or radiosurgery 184. In a study
conducted to assess the outcome of surgical treatment
at the University of California, San Francisco, USA,
232 patients were selected with a mean age of 38 years,
Lawton–Young grades of ≤III (69% of patients) and few
(<4%) arteriovenous malformations in deep locations.
Embolization was used as a preoperative adjunct in just
43% of patients and did not result in complications.
Postoperative angiography confirmed that all patients
were cured by the surgical intervention. 78% of all
patients and 91% of patients with unruptured arterio­
venous malformations experienced good outcomes
(mRS (modified Rankin Scale) scores 0–1). These sur-
gical results are consistent with other reports in the lit-
erature. For example, in a review of 1,235 patients with
low-grade arteriovenous malformations, the average sur-
gical morbidity and mortality rates were 2.2% and 0.3%,
respectively, with an average cure rate of 98.5% and a
postoperative or delayed haemorrhage rate of 0.3%110.
PRIMER
a surgery still offers the best cure rate, lowest risk profile
AVM AVM
* increased the risk of stroke or death in patients with
*
b arteriovenous malformations (ARUBA) 13 involved
Figure 8 | Tectal arteriovenous malformations treated with Gamma
Nature | Disease Primers
Reviews Knife
stereotactic radiosurgery.  a | Targeting is based on digital subtraction angiography,
which visualizes the basilar artery (marked by an asterisk), the feeding arteries and nidus
(arrows). b | MRI is also used to increase precision. Yellow and green lines around the
arteriovenous malformation (AVM) mark the isodose lines, which are contoured to limit
radiation to surrounding brain structures.
The management of arteriovenous malformations
outside the United States is diverging from the micro­
surgical approach. In some European countries, for
example, treatment is often limited to ruptured arterio-
venous malformations and involves aggressive emboli-
zation, frequently adding radiosurgery when the latter
was incomplete. However, cure rates with Onyx embo-
lization are still low and are associated with increased
complications, such as the occlusion of critical draining
veins and adverse imaging findings, such as ischaemia
or infarctions, in as many as 40% of patients. In a review
of 1,297 patients with mostly low-grade arteriovenous
malformations, the average endovascular morbidity and
mortality rates were 6.2% and 1.6%, respectively, with
an average cure rate of only 29% and a postoperative or
delayed haemorrhage rate of 8.0%. These figures show
that aggressive embolization has higher procedural
risks, lower cure rates and increased haemorrhage risks
c­ompared with microsurgery.
Radiosurgery also ranks below microsurgery in the
management protocol of low-grade arteriovenous mal-
formations. Although these lesions are ideal for radio-
surgery because of their lower target volumes and higher
obliteration rates, the 2–3 year latency period between
treatments and obliteration opens the possibility for
haemorrhage and associated complications. Radiation-
induced complications are low, but in a review of 1,051
patients with low-grade arteriovenous malformations,
7.2% of patients haemorrhaged after treatment, result-
ing in morbidity and mortality rates of 6.5% and 1.2%,
respectively 110. The 75.2% cure rate for radiosurgery was
superior to the cure rate for endovascular interventions
but was still lower than microsurgery. Thus, despite the
advances in endovascular and radiosurgical therapy,
14 | 2015 | VOLUME 1 www.nature.com/nrdp
© 2015 Macmillan Publishers Limited. All rights reserved
and greatest protection against haemorrhage for low-
grade arteriovenous malformations. Surgery cannot
compete with the minimally invasive appeal of these
other modalities, but this issue remains secondary to
functional outcome.
Controversy arose following a 2014 randomized con-
trolled clinical trial showing that interventional therapy
arteriovenous malformations compared with medical
treatment. The randomized trial of unruptured brain
223 patients and was designed to compare pharmacologi-
cal therapy for neurological symptoms (as needed; control
group) with an interventional group of patients under-
going neurosurgical, endovascular or radio­therapy pro-
cedures (alone or in combination; experimental group).
Unexpectedly, the trial showed that the control group had
better outcomes than those assigned to interventional
therapy, with stroke and death rates of 10.1% and 30.7%,
respectively 13. A planned interim analysis even showed
that the risk of death and symptomatic stroke was 73%
lower for patients allocated to non-­intervention com-
pared with the experimental group (HR in the popula-
tion as randomized 0.27; 95% CI: 0.14–0.54; HR in the
population as actually treated 0.19; 95% CI: 0.09–0.38). In
addition, the risk of neurological impairment (mRS ≥2)
decreased by 60% after 12 months (relative risk (RR) 0.4;
95%: CI 0.1–0.8) and by 80% after 2 years (RR 0.2; 95% CI
0.1–0.6) for the non-interventional group compared with
the interventional group. Similar results were reported in
a 12‑year prospective observational study in a Scottish
cohort of unruptured brain arteriovenous malforma-
tions24. In this study, the risk of stroke and neurological
deficits remained 63% lower for unruptured brain arterio-
venous malformations managed conservatively (HR: 0.37;
95% CI: 0.19–0.72) compared with surgical intervention24.
Despite its evident results, the ARUBA study received
profound criticism. Defenders of the trial results argue
that patients enrolled were representative of population-
based cohorts, that arteriovenous malformations had
profiles favouring treatment (62% being <3 cm in dia­
meter), that an interim analysis only provides an interim
distribution of treatment modalities, and that the study
was not powered to evaluate neurosurgical outcome
alone185. However, the study had a number of weaknesses.
First, a considerable number of neurosurgical investiga-
tors did not consider arteriovenous malformations with
low Spetzler–Martin grades (low treatment risk) to be in
equipoise with observational management alone owing
to the high haemorrhage risk and treated the patients
regardless, thereby excluding these patients from enrol-
ment. Furthermore, patients with inter­mediate- and
high-grade arteriovenous malformations that are gen-
erally considered to have a benign natural history, but
are at high risk for any treatment, were included in the
trial, which might have diminished the interventional
results186. Second, with its bias towards non-surgical
therapy, the number of incompletely obliterated arterio­
venous malformations that remained after treatment
was probably substantial and resulted in ruptures during

the study period. Thus, the adverse events in the inter-
ventional group reflected the procedural morbidity
of the therapies during the trial compounded with the
delayed morbidity of latent haemorrhages associated with
radiosurgery and incomplete embolization in the past.
The outcomes of such a group with many incompletely
treated malformations could never be superior to those
of an observational group whose only morbidity was the
natural history risk. Third, non-surgical preferences in
the ARUBA trial are apparent. Two-thirds of patients
in the interventional group had low-grade, surgical
arteriovenous malformations and yet only 18% under-
went surgery, whereas 32% were treated with emboliza-
tion alone, 33% with radio­surgery alone and 16% with
a combination of both. Thus, the threefold increase in
death or stroke in the interventional group potentially
reflects the risks associated with embolization and radio-
surgery therapies, rather than micro­surgery. Indeed, the
rates of stroke and death in this trial do not match other
reported surgical outcomes. In addition, centres were
required to manage ten patients with arteriovenous mal-
formations per year, but there were no minimum require-
ments for neurosurgeons; arteriovenous malformation
resection is among the most challenging neuro­surgical
cases, and high-volume surgeons typically perform
>25 resections annually.
These critiques were validated in an analysis of
ARUBA-eligible patients managed outside the trial. As
a participating ARUBA site, the University of California,
San Francisco, screened 473 patients for eligibility but
enrolled only 4 patients in the trial; 74 eligible patients
were managed outside the trial. Of these 74 patients,
43 patients (71% of treated patients) were treated surgi-
cally, 15 patients (25% of treated patients) were treated
radiosurgically and 13 patients (18% overall) were
observed. The risk of stroke and death among treated
patients was lower than in ARUBA, with primary out-
come rates of 11%, 27% and 8% for surgery, radiosurgery
and observation, respectively. The threefold difference in
primary outcome reported in ARUBA disappeared with
a different management strategy and a different surgical
expertise, leaving no significant difference in the rate of
stroke or death between treated and observed patients.
Thus, results in ARUBA-eligible patients managed out-
side that trial led to an entirely different conclusion about
intervention in arteriovenous malformations manage-
ment, owing to the primary role of surgery, judicious
surgical selection with established outcome predictors
and technical expertise developed at a high-volume
a­rteriovenous malformation centre184.
Quality of life
Although health-related quality of life measures are
increasingly used as part of neurological treatment t­rials
and large observational studies, scant data are available in
relation to the management of arteriovenous malforma-
tions. The most prevalent outcome scale used to reflect
neuro­logical impairment in neurovascular research is the
mRS, which is scored from 0 to 6, where a mRS score of 0
is normal, mRS of 1 reflects symptoms without physi­
cal deficit or interference with usual activities, mRS of 2
NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 15
© 2015 Macmillan Publishers Limited. All rights reserved
PRIMER
reflects a neurological deficit that interferes with usual
activities but not with self-care, progressing to mRS of 6,
death. More detailed health-related quality of life instru-
ments, such as the SF‑36 and EuroQoL187, have been
established in arteriovenous malformation research as
part of the ARUBA trial protocol, and their widespread
use would be desirable even though the complex­ity of
their administration might negatively influence com-
pliance of patients and clinicians. The little evidence
that exists suggests that following microsurgery, a mRS
score <2 correlates with good neuropsychological and
p­sychosocial outcomes188.
For arteriovenous malformations presenting without
haemorrhage and managed conservatively, approxi-
mately 98% and 80–90% will remain haemorrhage-free
after 12 months and 10 years, respectively. Following
rupture, 96% and 65% will remain haemorrhage-free
after 12 months and 10 years, respectively, when left
untreated12,14,189,190 (FIG. 9). The risk of subsequent bleeding
further increases in the presence of ruptured-­associated
aneurysms, deep location, exclusively deep venous drain-
age and increasing patient age12,15,17,191. However, initial
haemorrhage remains the strongest predictor 12,14, and
some of the additional factors might be biased by dif-
ferential censoring owing to differences in the degree
of surgical difficulty (deep venous drainage is likely to
be managed conservatively) or long-term benefit (older
patients are likely to be managed conservatively). Some
prospective population data suggest the 12‑month case-
fatality after haemorrhage is 12% overall, with increasing
patient age and initial haematoma volume as independent
predictors21. In arteriovenous malformations diagnosed
unruptured, the 12‑year risk of death was not different
for conservatively managed patients compared with those
with intervention (adjusted HR: 1.62; 95% CI: 0.72–
3.65)24. Several studies showed that clinical outcome after
rupture is better than after hypertension-related haemor­
rhage, independent of patient age and other known
p­redictors of intracerebral haemorrhage outcome21,192.
In addition to haemorrhage, health-related quality
of life might be affected by seizures, neurological defi-
cits unrelated to seizure (that is, hemiparesis and homo­
nymous haemianopia) and headaches. Generalized
s­eizures unrelated to haemorrhage occur in 30% of
patients with arteriovenous malformations; focal s­eizures
occur in 10%6. For patients with seizures, the 5‑year
chance of achieving a seizure-free period of 2 years with
anti­epileptic drugs is 40–80%, but the success is indepen­
dent of interventional therapy 25,193,194. Neurological defi-
cits can also be caused by alterations in regional brain
blood flow, which are caused by the variable interaction
between regional pressure reduction in arteries and eleva-
tion in veins, and they can be progressive (4–6% of new
arterio­venous malformations), persistent (6–9% of
new cases) or transient (6–10% of new cases)6. Headaches
unrelated to haemorrhage occur in 12–16% of patients6.
The headache types can vary and include migraine,
tension-type headaches and other subtypes. In cases
of migraine, the arterio­venous malformation u­sually
has an external carotid supply and is more c­ommonly
located posteriorly 6.
 PRIMER
70
Cumulative risk of rupture (%)
60 Kim et al. (2014) Previously ruptured
Gross et al. (2014) AVMs
50
40
30 Unruptured AVMs
20
10
0 away tip for more aggressive embolization with reduced
0 5 10 15 20
Years
Figure 9 | Hypothetical cumulative risk of rupture in patients
Nature with| arteriovenous
Reviews Disease Primers
malformations.  The graph shows the cumulative risks of ruptures of arteriovenous
malformations (AVMs) with and without a previous haemorrhage. Percentage
cumulative risk of rupture was calculated as (1 – e−annual rate × years) × 100. Kim et al.12
reported a 4.8% risk of rupture for previously ruptured AVMs and a 1.3% risk for
unruptured AVMs, respectively, whereas Gross et al.196 reported a 4.5% and 2.2% of
risk for previously ruptured and unruptured AVMs, respectively.
Although living with an untreated brain arterio-
venous malformation carries the potential risks cited
above, treatment can also be associated with manifest
adverse effects. A systematic meta-analysis incorporat-
ing 13,698 patients with arteriovenous malformations
including 46,314 patient-years of follow‑up data suggest
that interventional therapy remains associated with con-
siderable risks and incomplete efficacy. Severe complica-
tion and complete obliteration rates of 6.6% and 13%,
respectively, were associated with endovascular therapy;
rates of 5.1% and 38%, respectively, were associated with
stereotactic radiosurgery; and rates of 7.4% and 96%,
respectively, were associated with microsurgery 195.
Another consideration relates to the risk of haemor-
rhage during pregnancy. Some retrospective cohort case
series suggest an increased rate of haemorrhage, lead-
ing to recommendations of arteriovenous malforma-
tion obliteration before pregnancy, avoidance of vaginal
delivery or pregnancy avoidance8,196. However, other
reports suggest no increased risk of arteriovenous mal-
formation rupture during pregnancy 19,197,198. Thus, this
issue remains controversial and we do not recommend
deviation from normal obstetric practice.
Outlook
Advances in surgical techniques
The management of brain arteriovenous malformations
continues to evolve with advances in micro­surgical,
radiosurgical and endovascular techniques and tech-
nology. Microsurgical results have improved over time
with the creation of newer grading systems to select
patients likely to experience optimal outcomes. Other
improvements include the following: the development
of instruments such as bipolar forceps and microclips
that coagulate or occlude feeding arteries effectively; the
recognition of arteriovenous malformation subtypes that
help to decipher the anatomy of the malformation; the
refinement of surgical approaches, strategies and dissec-
tion techniques that facilitate safe resection; and the use
of functional MRI to better identify and protect eloquent
16 | 2015 | VOLUME 1 www.nature.com/nrdp
© 2015 Macmillan Publishers Limited. All rights reserved
areas95,97. Endovascular results have also improved over
time, perhaps even more dramatically. Onyx represents
a quantum leap in liquid embolysates over polyvinyl
alcohol (PVA) and NBCA glue. The higher viscosity of
Onyx enables it to slowly reach draining veins, its non-­
adherence causes less catheter retention and its slow
solidification deepens nidal penetration. Advances in
liquid embolysates are anticipated to increase penetra-
tion and durability over time. Improved microcatheters
are also expected, such as one with a detachable break­
complications from retained catheters. Transvenous
approaches to embolization have been introduced for
some arteriovenous malformations (small, deep, unrup-
tured and refractory to radio­surgical obliteration). They
include navigating against flow into the nidus by way
of its dilated draining veins and using systemic hypo-
tension or balloon occlusion of large feeding arteries to
reduce antegrade flow through the nidus. This technique
carries a risk of perforating the draining vein, premature
occlusion and intraprocedural haemorrhage, making it
an experimental technique that remains to be proven.
However, it exemplifies the type of innovation that is
possible with endovascular techniques. Improvements
in endovascular management will hopefully decrease
its complication rate and increase its cure rate, and
will make it a competitive, less invasive a­lternative to
open microsurgery.
Advances in drug development
Drug development for the pharmacological manage-
ment of arteriovenous malformations has been slower
than advances in the surgical and endovascular arenas.
To date, there are no specific or approved therapies;
however, drug development has been envisioned in
several forms, including preventing the formation of
arteriovenous malformations, inducing obliteration
and stabilizing vessels to reduce rupture risk199. These
therapies depend on improved understanding of the the
under­lying mechanisms of arteriovenous malforma-
tion development. Walker et al.200 recently developed
the first credible adult mouse model of arteriovenous
malformations using angiogenic stimulation with
VEGF in combination with conditional deletion of Alk1
to induce severe vascular dysplasia with arteriovenous
shunting in a nidus-like lesion in the brain (FIG. 3a).
A similar model with conditional deletion of Eng also
produced an arterio­venous lesion in the mouse brain
mimicking an arteriovenous malformation. These
developments validate the genetic mechanisms respon-
sible for the formation of arteriovenous malformations
in patients with hereditary haemorrhagic telangiectasia
and also have implications for sporadic arteriovenous
malformations. Furthermore, these models support the
response-to-injury hypothesis and, importantly, provide
an experimental system for testing new pharmacological
interventions. For example, VEGFR1 (encoded by FLT1)
has anti-angiogenic properties. Expression of soluble
VEGFR1 has been shown to abolish VEGF-induced
angiogenesis and the formation of arteriovenous mal-
formations in mice, suggesting a novel treatment.
 PRIMER

Similarly, bevacizumab has been demonstrated to pre-
vent or halt the progression of both cutaneous and brain
arteriovenous malformations in animal models200,201.
Tetracycline and doxycycline inhibit matrix metallo-
proteinases, which might stabilize arteriovenous mal-
formations and reduce vascular degradation202,203. These
common antibiotics are taken up in malformations and
might provide some reduction in haemorrhage risk in
patients whose arteriovenous malformations are man-
aged conservatively. These experimental studies remain
in their infancy and have yet to progress to clinical trials,
but they signal that translational research is advancing
for the first time. Genetic studies and the discovery of
genes involved in sporadic arteriovenous malformations
might offer additional insight into their biology and
inform the the design of future therapies that obliterate,
stabilize or regress the malformations.
and prostate. Now, the identification of molecular and
genetic pathways for cancer has shifted focus to the geno­
typical causes. Any single genetic signature or signalling
pathway in cancer can be relevant for multiple organ-
specific cancer phenotypes. For example, activated muta-
tions in GNAQ were first described in uveal melanoma
but have been observed in multiple additional tumour
types206–208, and now also in Sturge–Weber syndrome54.
As research advances our understanding of the
pathophysiology of arteriovenous malformations, grad-
ing systems must evolve and incorporate these advances,
such as genetic information and biological markers.
Haemodynamic data might also become a defining ele-
ment of rupture risk and future grading scales. Thus,
the work of developing new grading systems should be
viewed as an ongoing process that will refine and reshape
existing grading systems.

Optimization of classification criteria Advances in clinical studies

Although the Spetzler–Martin grading scale is well
established to evaluate the risks of microsurgery, it
is not a relevant predictor of the risks associated with
embolization or radiosurgery. These observations have
led to the development of endovascular and radio-
surgical grading systems204,205. Interventional grading
systems need indivi­dualized predictors of the natural
history of arterio­venous malformations. The current
grading s­ystems are generally useful but are imperfect
and evolving.
In addition, mutations in arteriovenous malforma-
tions and other vascular malformations might have
overlapping genetic signatures, and these canonical
molecular pathways may be relevant to several types
of vascular malformations. Analogously, the oncology
field initially focused on phenotypical descriptions of
c­ancers in the organs of origin such as the breast, lungs
Finally, it will be important for investigators to continue
to perform robust clinical studies and randomized trials
to further refine indications for treatment. The ARUBA
trial and the controversy surrounding it has reminded
the community of its obligation to continue question-
ing best practices. For example, some critics of the
ARUBA trial have suggested that another trial is needed
to re‑establish the role of surgery in management called
BARBADOS (Beyond ARUBA — Randomized low-
grade Brain AVM stuDy, Observation versus Surgery)209.
Other critics have begun organizing prospective regis-
tries of patients with arterio­venous malformations for
detailed outcome analyses. The future of arteriovenous
malformation research, whether at the bench or bed-
side, will depend on well-defined and objective efforts
to b­etter understand and manage this fascinating disease
and prevent its potentially devastating complications.

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Acknowledgements
This primer cites research that was supported in part by US
National Institutes of Health grants: R01 NS034949 (H.K.)
and U54 NS065075 (M.T.L.). The Brain Vascular Malformation
Consortium (U54NS065075) is part of the Rare Diseases
Clinical Research Network (RDCRN), an initiative of the Office
of Rare Diseases Research (ORDR) that is funded through
c­o llaboration between National Center for Advancing
Translational Sciences (NCATS) and the National Institute of
Neurological Disorders and Stroke (NINDS).
Author contributions
Introduction (M.T.L.); Epidemiology (W.C.R., H.K. and C.S.);
Mechanisms/pathophysiology (K.J.W., D.Y.L. and H.K.);
Diagnosis, screening and prevention (T.K. and K.T.B.);
Management (M.T.L., T.K., K.T.B. and D.K.); Quality of life
(M.K.M.); Outlook (K.M., R.F.S., M.T.L. and H.K.); overview of
Primer (M.T.L.).
Competing interests statement
The authors declare no competing interests.