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Cerebral Arteriovenous Malformation Diagnosis and Management

Article  in  Seminars in Neurology · November 2013

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


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3 authors, including:

Kaiz Asif
Medical College of Wisconsin


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Cerebral Arteriovenous Malformation Diagnosis

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

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

Semin Neurol 2013;33:468–475.

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

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

Issue Theme Advanced Cerebrovascular Copyright © 2013 by Thieme Medical DOI
Disease Management; Guest Editor, Jason Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0033-1364212.
Mackey, MD, MS New York, NY 10001, USA. ISSN 0271-8235.
Tel: +1(212) 584-4662.
Cerebral Arteriovenous Malformation Diagnosis and Management Asif et al. 469

lesions rarely occur spontaneously and are most commonly the abnormal hemodynamic condition, feeding arteries and
observed in syndromic settings with cutaneous or extracra- draining veins become progressively dilated and tortuous.
nial vascular anomalies18 such as Rendu-Osler-Weber disease Normal vascular structures undergo a series of secondary
and Wyburn-Mason syndrome. changes. Feeding arteries may be one or numerous and
Brain AVMs are often pyramid-shaped such that the base is experience high flow arteriovenous shunting due to absence
adjacent the cortex and the vertex projects internally toward of capillary networks. Because of constant intraluminal stress
the ventricles. Arteriovenous malformations are further dif- there is abnormal dilation, degenerative changes with aber-
ferentiated anatomically based on the involvement of brain rant elastic lamina, variability of medial thickness in the
parenchyma. A compact nidus is a malformed capillary bed vessel wall, and architectural disarray.2,20–22 High flow may
that is tightly organized such that normal brain parenchyma result in new pathology such as saccular aneurysm formation.
is displaced. A diffuse nidus is loosely organized with sparse, These aneurysms can be located at the level of the circle of
abnormal AV channels such that normal brain parenchyma Willis, the feeding arteries, or within the nidus.23–26 Addi-
persists.19 The appearance of an AVM on catheter angiogra- tionally, high flow can produce progressive stenosis and
phy can highlight these characteristics (►Fig. 1). eventual occlusion of feeding arteries.27 Draining veins can
The velocity of blood flow is considerably higher through be single or multiple, deep or cortical, and are also exposed to
AVMs than through normal brain parenchyma. As a result of increased intraluminal stress. Direct shunting of blood at
arterial pressure causes dilatation, thickening, and tortuosity
in the involved veins. High flow may also produce localized
stenosis, frequently at the level where the veins cross the dura
to reach the sinus,28,29 and secondary venous aneurysmal

Establishing a true prevalence of AVM is difficult because of
the rarity of the disease and the presence of asymptomatic
patients; prevalences are likely underestimates. Large post-
mortem studies are still needed. Only a few hospital-based
postmortem studies are available, reporting a prevalence
between 400 and 600 per 100,000.22,31,32 Much of what is
known about incidence is from population-based studies.
Over a 10-year-period in the Netherlands Antilles, the annual
incidence of symptomatic AVMs was 1.1 per 100,000 per
year.33 In another study, the incidence of symptomatic AVMs
was 1.84 per 100,000 per year.34 The New York Islands AVM
Study, a prospective population-based incidence and case-
control study, found an annual AVM detection rate of 1.34 per
100,000 person-years. Arteriovenous malformations are
found incidentally on 0.05% of brain magnetic resonance
imaging (MRI) screens.35 There are very few familial cases.
Arteriovenous malformations are more commonly identified
in younger individuals. Detection in utero or in infancy is
rare,36–38 and the diagnosis is most commonly made between
30 and 40 years of age. Both sexes are affected in nearly equal

Clinical Presentation
The clinical presentation of these lesions can vary and
include signs of intracranial hemorrhage (focal deficits,
nausea, vomiting, etc.), seizures, and headaches. Intracra-
nial hemorrhage is a common cause of symptomatic pre-
sentation,40 and often is the presenting feature in the
second through fourth decades of life.41 Seizures at pre-
Fig. 1 A high-frame-rate catheter angiogram captures several distinct
sentation have been reported to occur in ! 30% of patients.
components of an arteriovenous malformation including feeding
artery supply (A, arrows), nidus (B, circle), and venous outflow
Headaches have been reported in 14% of patients.39 The
(C, arrow ), which must be separated by fractions of a second due to the clinical presentation may be affected by the size and loca-
high flow. tion of the lesion.

Seminars in Neurology Vol. 33 No. 5/2013

470 Cerebral Arteriovenous Malformation Diagnosis and Management Asif et al.

Diagnosis intranidal gliosis, parenchymal atrophy with focal dilatation

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

Computed Tomography and Magnetic

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

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

Seminars in Neurology Vol. 33 No. 5/2013

Cerebral Arteriovenous Malformation Diagnosis and Management Asif et al. 471

tem. It added three more variables: Age (< 20 years: 1 point,

Functional Imaging
20–40 years: 2 points, > 40 years: 3 points), prior history of
Assessment of the eloquence of brain tissue involved with rupture (ruptured: 0 points, not ruptured: 1 point), degree of
AVMs with blood-oxygen-level dependent (BOLD) functional diffuseness (compact: 1 point, diffuse: 0 point) with grades
MRI could help in avoiding damage to the eloquent brain ranging from I to V. They analyzed a consecutive surgical
areas before embolization, surgical resection, or radiosurgery. series of 300 patients to compare the predictive accuracy
In this way BOLD can help shorten the surgical time and using the Spetzler-Martin scale and the supplementary scale
achieve smaller craniotomies.50,51 One of the major limita- and found the scale had high predictive accuracy and strati-
tions of the task-based functional MRI for AVMs and vascular fied surgical risk more evenly. The supplementary grade can
tumors is the phenomenon of neurovascular uncoupling, be considered separately, with supplementary grades I to III
which occurs when dysplastic vessels do not demonstrate having an acceptably low risk of AVM resection. The supple-
appropriate BOLD activation of the normal functioning mentary scale can also be added to the Spetzler-Martin grade,
neurons.52 with combined grades 1 to 6 having an acceptably low
surgical morbidity. In cases of mismatched Spetzler-Martin
and supplementary grades, the supplementary grading sys-
Natural History
tem can potentially play a role in altering clinical decisions,
For unruptured AVMs, the rate of rupture has not been well- though more data on the application of this grading system is
defined, though reports include annual risks of up to 2 to 4% in required.57
patients with an initial nonhemorrhagic presentation and a A separate classification system for grading in endovas-
widely varying lifetime risk of hemorrhage estimated to be 17 cular therapy has also been proposed. This classification
to 90%.53 High-risk features for rupture including nidal system includes AVM size, number of feeding arteries, and
aneurysms and angiographic flow characteristics are often pial versus perforating feeding arteries. Low-grade AVMs that
considered, but consensus on the importance of these fea- were considered suitable for endovascular therapy were
tures has not been established. For ruptured AVMs, the risk of small, had fewer than two feeding arteries, and were not
rehemorrhage after first hemorrhagic presentation has been supplied by perforators, whereas high-grade AVMs that were
reported as 6 to 18% in the first year, after which it is ! 2% per large (> 4 cm), had more than four feeding arteries, and were
year for the next 20 years.54 supplied by perforators were not suitable for endovascular

Classification Systems
The Spetzler-Martin classification is used to grade AVMs
based on their degree of surgical difficulty and the risk of Due to the lack of robust natural-history data and the limited
surgical morbidity and mortality. The grade is based on the understanding of features thought to be associated with a
size of the AVM (< 3 cm: 1 point, 3–6 cm: 2 points, > 6 cm: 3 high risk of hemorrhage, the management of AVMs remains
points), venous drainage (superficial only: 0 points, deep: 1 complex. The choice between procedural management and
point) and eloquence of adjacent brain (eloquent: 0 points, observation with medical management and radiologic sur-
noneloquent: 1 point), with grades ranging from I to V. veillance is not always clear-cut. The high morbidity and
Arteriovenous malformations too complex for resection, in- mortality associated with ruptured AVMs often warrants a
cluding brainstem and holohemispheric AVMs, were given procedural approach, with the goal of AVM eradication.
grade VI. Low-grade AVMs (grades I and II) have relatively low Treatment modalities include endovascular embolization,
surgical morbidity rates and are commonly treated surgically, surgical resection, and radiosurgical intervention. Random-
while high-grade AVMs (grades IV and V) have relatively high ized studies comparing treatment approaches are lacking.
surgical morbidity rates and are commonly managed The specifics of each case are considered and a tailored team-
conservatively. based approach is often required.
Grade III AVMs are somewhat more challenging and are
the most heterogeneous of the five grades.55 Grade III AVMs Observation
have been further divided into four different combinations: Unruptured AVMs with a nonhemorrhagic presentation are
small-deep-eloquent (S1V1E1), medium-deep (S2V1E0), me- often considered for observation, which includes medical
dium-eloquent (S2V0E1), and large (S3V0E0). Based on a management and surveillance imaging. The ARUBA (A Ran-
consecutive series of 76 grade III AVMs, Lawton et al found domized Trial of Unruptured Brain Arteriovenous Malforma-
that neurologic outcomes varied according to the subtype of tions) Trial compared medical management with invasive
grade III AVM. They found that small-deep-eloquent (S1V1E1) treatment in patients with unruptured AVMs. The ARUBA
AVMs had surgical risks similar to low-grade AVMs, but that Trial halted enrollment after a preplanned interim data safety
medium-eloquent (S2V0E1) AVMs had surgical risks similar monitoring board review identified a higher event rate in the
to high-grade AVMs. Medium-deep (S2V1E0) had intermedi- intervention group compared with medical management.59
ate surgical risks.56 Although early event rates were higher in the intervention
Lawton and colleagues subsequently introduced a supple- arm, patients will be followed to determine whether the
mentary grading system to the Spetzler-Martin grading sys- difference in stroke and death in the two arms changes

Seminars in Neurology Vol. 33 No. 5/2013

472 Cerebral Arteriovenous Malformation Diagnosis and Management Asif et al.

over time. Medical management for symptomatic unruptured

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

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

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

Seminars in Neurology Vol. 33 No. 5/2013

Cerebral Arteriovenous Malformation Diagnosis and Management Asif et al. 473

Table 1 Treatment approaches for cerebral arteriovenous malformations

Approach Benefits Limitations

Endovascular Catheter delivery of Minimally invasive Obliteration rate can be
embolization Real-time angiography lower depending on characteristics
• Liquid embolics (n-butyl Risk of ischemic complications
cyanoacrylate glue, Onyx) during treatment
• Coils

Surgical resection Microsurgical excision High rates of complete Invasive due to craniotomy
Radiotherapy Focal radiation is administered Noninvasive 1–3 year latency for obliteration
to the lesion Parenchymal radiation injury
Limited to smaller lesions

radiosurgery, the target of embolization is often the periph- thalamus/basal ganglia/brainstem]).72 The proportion of
ery of the AVM to reduce the size and therefore the total AVMs obliterated without a new neurologic deficit was
radiation dose required.61,62 Clinically significant complica- greater than 90% for a score less than 1 and less than 40%
tions have been reported to occur in ! 6.5% cases.63 for a score more than 2.73
Various approaches for treatment of AVMs continue to
Surgical Resection develop and often involve complementary interventions in
Microsurgical excision involves creating a craniotomy cen- complex lesions to afford a greater success rate (►Table 1).
tered over the nidus followed by careful devascularization of
the AVM by occluding the arterial feeders. Circumferential
separation of the AVM from the adjacent parenchyma is
performed and the draining veins are then divided.64 Intra- Arteriovenous malformations are rare developmental vascu-
operative electrophysiologic monitoring is often performed lar lesions that often present in younger individuals with
using electroencephalography, somatosensory evoked poten- intracranial hemorrhage, seizure, or headaches. Rates of
tials, and in the case of posterior fossa AVMs, brainstem intracranial hemorrhage are low, but high morbidity and
auditory evoked potentials.65 Postoperative angiography is mortality necessitate a careful consideration of management
performed to confirm complete excision. risks and benefits. Current treatment approaches include
The risk of microsurgical approach is assessed using the medical management, endovascular liquid embolization, fo-
Spetzler-Martin grading system with higher grades associat- cal radiosurgery, and surgical resection.
ed with greater surgical morbidity and mortality.55,66 A meta-
analysis reviewing several series from 1990 to 2000 showed a
mean global mortality of 3.3% and mean postoperative global
morbidity of 8.6%.67
1 The Arteriovenous Malformation Study Group. Arteriovenous
malformations of the brain in adults. N Engl J Med 1999;
Stereotactic Radiotherapy 340(23):1812–1818
Stereotactic radiosurgery aims at achieving progressive oblit- 2 Rosenblum M, Bilbao J, Ang L, et al. Central nervous system.
eration of an AVM using intense high-dose radiation pro- Ackerman’s Surgical Pathology. 8th ed. St Louis, MO: Mosby;
duced by a radiation source (including gamma knife, linear 1996:2238
3 Challa VR, Moody DM, Brown WR. Vascular malformations of the
accelerators, or proton-beam) and delivered accurately and
central nervous system. J Neuropathol Exp Neurol 1995;54(5):
precisely using a navigation system (►Fig. 4). Obliteration of 609–621
the AVM occurs via endothelial damage and thickening of 4 Shalaby F, Rossant J, Yamaguchi TP, et al. Failure of blood-island
intimal layer followed by thrombosis and necrosis of AVM formation and vasculogenesis in Flk-1-deficient mice. Nature
vessels,68 a process which takes ! 2 to 3 years with a median 1995;376(6535):62–66
of !2 0 months required to obtain subtotal (> 95%) oblitera- 5 Patan S. TIE1 and TIE2 receptor tyrosine kinases inversely regulate
embryonic angiogenesis by the mechanism of intussusceptive
tion.69,70 The nidus geometry and neighboring at-risk struc-
microvascular growth. Microvasc Res 1998;56(1):1–21
tures are determined using thin-slice MRI and CT, which are 6 Fong GH, Rossant J, Gertsenstein M, Breitman ML. Role of the Flt-1
used to formulate radiosurgery treatment plans. receptor tyrosine kinase in regulating the assembly of vascular
Successful obliteration with radiosurgery is dependent on endothelium. Nature 1995;376(6535):66–70
various factors, including nidus volume, nidus density, radia- 7 Sato TN, Tozawa Y, Deutsch U, et al. Distinct roles of the receptor
tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature
tion dose, and location.71 The modified radiosurgery-based
grading scale incorporates some of these factors and is
8 Uranishi R, Baev NI, Ng PY, Kim JH, Awad IA. Expression of
calculated as follows: (0.1 " volume in mL) þ (0.02 " age endothelial cell angiogenesis receptors in human cerebrovascular
in years) þ (0.5 " location [0 for hemispheric/intraventricu- malformations. Neurosurgery 2001;48(2):359–367, discussion
lar/callosal/cerebellar AVMs and 1 for AVMs involving the 367–368

Seminars in Neurology Vol. 33 No. 5/2013

474 Cerebral Arteriovenous Malformation Diagnosis and Management Asif et al.

9 Hashimoto T, Emala CW, Joshi S, et al. Abnormal pattern of Tie-2 bral arteriovenous malformation. Neurosurgery 2000;46(2):
and vascular endothelial growth factor receptor expression in 272–279, discussion 279–281
human cerebral arteriovenous malformations. Neurosurgery 30 Nataf F, Meder JF, Roux FX, et al. Angioarchitecture associated with
2000;47(4):910–918, discussion 918–919 haemorrhage in cerebral arteriovenous malformations: a prog-
10 Novakovic RL, Lazzaro MA, Castonguay AC, Zaidat OO. The diag- nostic statistical model. Neuroradiology 1997;39(1):52–58
nosis and management of brain arteriovenous malformations. 31 Berman MF, Sciacca RR, Pile-Spellman J, et al. The epidemiology of
Neurol Clin 2013;31(3):749–763 brain arteriovenous malformations. Neurosurgery 2000;47(2):
11 Stapf C, Mohr JP, Sciacca RR, et al. Incident hemorrhage risk of brain 389–396, discussion 397
arteriovenous malformations located in the arterial borderzones. 32 Al-Shahi R, Warlow C. A systematic review of the frequency and
Stroke 2000;31(10):2365–2368 prognosis of arteriovenous malformations of the brain in adults.
12 Vander Eecken HM, Adams RD. The anatomy and functional Brain 2001;124(Pt 10):1900–1926
significance of the meningeal arterial anastomoses of the human 33 Jessurun GA, Kamphuis DJ, van der Zande FH, Nossent JC. Cerebral
brain. J Neuropathol Exp Neurol 1953;12(2):132–157 arteriovenous malformations in The Netherlands Antilles. High
13 Jeffree RL, Stoodley MA. Postnatal development of arteriovenous prevalence of hereditary hemorrhagic telangiectasia-related sin-
malformations. Pediatr Neurosurg 2009;45(4):296–304 gle and multiple cerebral arteriovenous malformations. Clin Neu-
14 Mullan S, Mojtahedi S, Johnson DL, Macdonald RL. Cerebral venous rol Neurosurg 1993;95(3):193–198
malformation-arteriovenous malformation transition forms. J 34 Brown RD Jr, Wiebers DO, Torner JC, O’Fallon WM. Incidence and
Neurosurg 1996;85(1):9–13 prevalence of intracranial vascular malformations in Olmsted
15 Lasjaunias P. A revised concept of the congenital nature of cerebral County, Minnesota, 1965 to 1992. Neurology 1996;46(4):949–952
arteriovenous malformations. Interv Neuroradiol 1997;3(4): 35 Morris Z, Whiteley WN, Longstreth WT Jr, et al. Incidental findings
275–281 on brain magnetic resonance imaging: systematic review and
16 Yasargil M. AVM of the brain, history, embryology, pathological meta-analysis. BMJ 2009;339:b3016
considerations, hemodynamics, diagnostic studies, microsurgical 36 Baird WF, Stitt DG. Arteriovenous aneurysm of the cerebellum in a
anatomy. Stuttgart, Germany: Thieme Medical Publishing; 1987 premature infant: report of a case. Pediatrics 1959;24:455–457
17 Deruty R, Pelissou-Guyotat I, Mottolese C, Bascoulergue Y, Amat D. 37 Suh DC, Alvarez H, Bhattacharya JJ, Rodesch G, Lasjaunias PL.
The combined management of cerebral arteriovenous malforma- Intracranial haemorrhage within the first two years of life. Acta
tions. Experience with 100 cases and review of the literature. Acta Neurochir (Wien) 2001;143(10):997–1004
Neurochir (Wien) 1993;123(3-4):101–112 38 Mullan S, Mojtahedi S, Johnson DL, Macdonald RL. Embryological
18 Salcman M, Scholtz H, Numaguchi Y. Multiple intracerebral arte- basis of some aspects of cerebral vascular fistulas and malforma-
riovenous malformations: report of three cases and review of the tions. J Neurosurg 1996;85(1):1–8
literature. Surg Neurol 1992;38(2):121–128 39 Hofmeister C, Stapf C, Hartmann A, et al. Demographic, morpho-
19 Chin LS, Raffel C, Gonzalez-Gomez I, Giannotta SL, McComb JG. logical, and clinical characteristics of 1289 patients with brain
Diffuse arteriovenous malformations: a clinical, radiological, and arteriovenous malformation. Stroke 2000;31(6):1307–1310
pathological description. Neurosurgery 1992;31(5):863–868, dis- 40 da Costa L, Wallace MC, Ter Brugge KG, O’Kelly C, Willinsky RA,
cussion 868–869 Tymianski M. The natural history and predictive features of
20 McCormick WF. The pathology of vascular (“arteriovenous”) mal- hemorrhage from brain arteriovenous malformations. Stroke
formations. J Neurosurg 1966;24(4):807–816 2009;40(1):100–105
21 Mandybur TI, Nazek M. Cerebral arteriovenous malformations. A 41 Graf CJ, Perret GE, Torner JC. Bleeding from cerebral arteriovenous
detailed morphological and immunohistochemical study using malformations as part of their natural history. J Neurosurg 1983;
actin. Arch Pathol Lab Med 1990;114(9):970–973 58(3):331–337
22 Jellinger K. Vascular malformations of the central nervous system: 42 Mossa-Basha M, Chen J, Gandhi D. Imaging of cerebral arteriove-
a morphological overview. Neurosurg Rev 1986;9(3):177–216 nous malformations and dural arteriovenous fistulas. Neurosurg
23 Meisel HJ, Mansmann U, Alvarez H, Rodesch G, Brock M, Lasjaunias Clin N Am 2012;23(1):27–42
P. Cerebral arteriovenous malformations and associated aneur- 43 Choi JH, Mohr JP. Brain arteriovenous malformations in adults.
ysms: analysis of 305 cases from a series of 662 patients. Neuro- Lancet Neurol 2005;4(5):299–308
surgery 2000;46(4):793–800, discussion 800–802 44 Brown RD Jr, Flemming KD, Meyer FB, Cloft HJ, Pollock BE, Link ML.
24 Lasjaunias P, Piske R, Terbrugge K, Willinsky R. Cerebral arteriove- Natural history, evaluation, and management of intracranial vas-
nous malformations (C. AVM) and associated arterial aneurysms cular malformations. Mayo Clin Proc 2005;80(2):269–281
(AA). Analysis of 101 C. AVM cases, with 37 AA in 23 patients. Acta 45 Mossa-Basha M, Chen J, Gandhi D. Imaging of cerebral arteriove-
Neurochir (Wien) 1988;91(1-2):29–36 nous malformations and dural arteriovenous fistulas. Neurosurg
25 Ogilvy CS, Stieg PE, Awad I, et al; Stroke Council, American Stroke Clin N Am 2012;23(1):27–42
Association. Recommendations for the management of intracra- 46 Friedlander RM. Clinical practice. Arteriovenous malformations of
nial arteriovenous malformations: a statement for healthcare the brain. N Engl J Med 2007;356(26):2704–2712
professionals from a special writing group of the Stroke Council, 47 Eddleman CS, Jeong HJ, Hurley MC, et al. 4D radial acquisition
American Stroke Association. Circulation 2001;103(21): contrast-enhanced MR angiography and intracranial arteriove-
Q1 2644–2657Q1 nous malformations: quickly approaching digital subtraction an-
26 Cunha e Sa MJ, Stein BM, Solomon RA, McCormick PC. The giography. Stroke 2009;40(8):2749–2753
treatment of associated intracranial aneurysms and arteriovenous 48 Bednarz G, Downes B, Werner-Wasik M, Rosenwasser RH. Com-
malformations. J Neurosurg 1992;77(6):853–859 bining stereotactic angiography and 3D time-of-flight magnetic
27 Mawad ME, Hilal SK, Michelsen WJ, Stein B, Ganti SR. Occlusive resonance angiography in treatment planning for arteriovenous
vascular disease associated with cerebral arteriovenous malfor- malformation radiosurgery. Int J Radiat Oncol Biol Phys 2000;
mations. Radiology 1984;153(2):401–408 46(5):1149–1154
28 Miyasaka Y, Yada K, Ohwada T, Kitahara T, Kurata A, Irikura K. An 49 Berger MO, Anxionnat R, Kerrien E, Picard L, Söderman M. A
analysis of the venous drainage system as a factor in hemorrhage methodology for validating a 3D imaging modality for brain
from arteriovenous malformations. J Neurosurg 1992;76(2): AVM delineation: application to 3DRA. Comput Med Imaging
239–243 Graph 2008;32(7):544–553
29 Mansmann U, Meisel J, Brock M, Rodesch G, Alvarez H, Lasjaunias P. 50 Latchaw RE, Hu X, Ugurbil K, Hall WA, Madison MT, Heros RC.
Factors associated with intracranial hemorrhage in cases of cere- Functional magnetic resonance imaging as a management tool for

Seminars in Neurology Vol. 33 No. 5/2013

Cerebral Arteriovenous Malformation Diagnosis and Management Asif et al. 475

cerebral arteriovenous malformations. Neurosurgery 1995;37(4): tion: multivariate analysis of predictive factors. Neurosurgery
619–625, discussion 625–626 2006;58(4):602–611, discussion 602–611
51 Petrella JR, Shah LM, Harris KM, et al. Preoperative functional MR 64 Pradilla G, Coon AL, Huang J, Tamargo RJ. Surgical treatment
imaging localization of language and motor areas: effect on of cranial arteriovenous malformations and dural
therapeutic decision making in patients with potentially resect- arteriovenous fistulas. Neurosurg Clin N Am 2012;23(1):
able brain tumors. Radiology 2006;240(3):793–802 105–122
52 Ulmer JL, Krouwer HG, Mueller WM, Ugurel MS, Kocak M, Mark LP. 65 Chang SD, Lopez JR, Steinberg GK. The usefulness of electrophysi-
Pseudo-reorganization of language cortical function at fMR imag- ological monitoring during resection of central nervous system
ing: a consequence of tumor-induced neurovascular uncoupling. vascular malformations. J Stroke Cerebrovasc Dis 1999;8(6):
AJNR Am J Neuroradiol 2003;24(2):213–217 412–422
53 Starke RM, Komotar RJ, Hwang BY, et al. Treatment guidelines for 66 Schaller C, Schramm J, Haun D. Significance of factors contributing
cerebral arteriovenous malformation microsurgery. Br J Neuro- to surgical complications and to late outcome after elective
surg 2009;23(4):376–386 surgery of cerebral arteriovenous malformations. J Neurol Neuro-
54 Fults D, Kelly DL Jr. Natural history of arteriovenous malformations surg Psychiatry 1998;65(4):547–554
of the brain: a clinical study. Neurosurgery 1984;15(5):658–662 67 Castel JP, Kantor G. [Postoperative morbidity and mortality after
55 Spetzler RF, Martin NA. A proposed grading system for arteriove- microsurgical exclusion of cerebral arteriovenous malformations.
nous malformations. J Neurosurg 1986;65(4):476–483 Current data and analysis of recent literature]. Neurochirurgie
56 Lawton MT; UCSF Brain Arteriovenous Malformation Study Proj- 2001;47(2-3 Pt 2):369–383Q2 Q2
ect. Spetzler-Martin Grade III arteriovenous malformations: sur- 68 Schneider BF, Eberhard DA, Steiner LE. Histopathology of arterio-
gical results and a modification of the grading scale. Neurosurgery venous malformations after gamma knife radiosurgery. J Neuro-
2003;52(4):740–748, discussion 748–749 surg 1997;87(3):352–357
57 Lawton MT, Kim H, McCulloch CE, Mikhak B, Young WL. A 69 Wowra B, Muacevic A, Tonn JC, Schoenberg SO, Reiser M, Herr-
supplementary grading scale for selecting patients with brain mann KA. Obliteration dynamics in cerebral arteriovenous mal-
arteriovenous malformations for surgery. Neurosurgery 2010; formations after cyberknife radiosurgery: quantification with
66(4):702–713, discussion 713 sequential nidus volumetry and 3-tesla 3-dimensional time-of-
58 Vinuela F, Duckwiler G, Guglielmi G. Intravascular embolization of flight magnetic resonance angiography. Neurosurgery 2009;64(2,
brain arteriovenous malformations. In: Maciuna R, ed. Endovas- Suppl):A102–A109
cular Neurological Intervention. Rolling Meadows, IL: The Ameri- 70 Steinberg GK, Chang SD, Levy RP, Marks MP, Frankel K, Marcellus
can Association of Neurological Surgeons; 1995:189–199 M. Surgical resection of large incompletely treated intracranial
59 Starke RM, Komotar RJ, Connolly ES. A randomized trial of un- arteriovenous malformations following stereotactic radiosurgery.
ruptured brain arteriovenous malformations. Neurosurgery 2013; J Neurosurg 1996;84(6):920–928
73(4):N13–N15 71 Starke RM, Komotar RJ, Hwang BY, et al. A comprehensive review
60 Yu SC, Chan MS, Lam JM, Tam PH, Poon WS. Complete obliteration of radiosurgery for cerebral arteriovenous malformations: out-
of intracranial arteriovenous malformation with endovascular comes, predictive factors, and grading scales. Stereotact Funct
cyanoacrylate embolization: initial success and rate of permanent Neurosurg 2008;86(3):191–199
cure. AJNR Am J Neuroradiol 2004;25(7):1139–1143 72 Wegner RE, Oysul K, Pollock BE, et al. A modified radiosurgery-
61 Le Feuvre D, Taylor A. Target embolization of AVMs: identification based arteriovenous malformation grading scale and its correla-
of sites and results of treatment. Interv Neuroradiol 2007;13(4): tion with outcomes. Int J Radiat Oncol Biol Phys 2011;79(4):
389–394 1147–1150
62 Krings T, Hans FJ, Geibprasert S, Terbrugge K. Partial “targeted” 73 Andrade-Souza YM, Zadeh G, Ramani M, Scora D, Tsao MN,
embolisation of brain arteriovenous malformations. Eur Radiol Schwartz ML. Testing the radiosurgery-based arteriovenous mal-
2010;20(11):2723–2731 formation score and the modified Spetzler-Martin grading system
63 Ledezma CJ, Hoh BL, Carter BS, Pryor JC, Putman CM, Ogilvy CS. to predict radiosurgical outcome. J Neurosurg 2005;103(4):
Complications of cerebral arteriovenous malformation emboliza- 642–648

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Q1: AU: The title in ref. 25 "Ogilvy, Stieg, Awad, et al, 2001" was updated, but differs from the author’s original: Stroke Council,
American Stroke Association. Recommendations for the management of intracranial arteriovenous malformations: A
statement for healthcare professionals from a special writing group of the stroke council, american stroke association.
Q2: AU: Medline reports the vernacular article title for ref. 67 "Castel, Kantor, 2001" is Morbidité et mortalité du traitement
chirurgical des malformations artérioveineuses cérébrales. Données actuelles et analyse de la littérature récente. (in

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