The Risk of Stroke or Clinical Impairment After Stereotactic
Radiosurgery for ARUBA-Eligible Patients
Bruce E. Pollock, MD; Michael J. Link, MD; Robert D. Brown, MD
Downloaded from http://stroke.ahajournals.org/ by guest on June 15, 2017
Background and Purpose—The best management of patients with unruptured brain arteriovenous malformations (BAVM)
is controversial. In this study, we analyzed the stroke rate and functional outcomes of patients having stereotactic
radiosurgery (SRS) for unruptured BAVM using the same eligibility criteria and primary end points as the ARUBA trial.
Methods—Retrospective observational study of 174 ARUBA-eligible patients having SRS from 1990 to 2005.
Results—The median follow-up after SRS was 64 months. Fifteen patients (8.7%) had a hemorrhagic stroke at a median
of 21 months after SRS. Six patients (3.5%) had a focal neurological deficit and 4 patients died (2.3%). The risk of
stroke or death was 10.3% at 5 years and 11.5% at 10 years. Twelve additional patients (6.9%) had a focal neurological
deficit from either radiation-related complications (n=7) or subsequent resection (n=5). The risk of patients’ having
clinical impairment (modified Rankin Score ≥2) was 8.4% at 5 years and 12.0% at 10 years. Increasing BAVM volume
was associated with both stroke or death (hazard ratio=1.06; 95% confidence interval, 1.0–1.11; P=0.04) and clinical
impairment (hazard ratio=1.06; 95% confidence interval, 1.01–1.09; P=0.01). The 10-year risk of stroke or death and
clinical impairment for patients with BAVM ≤5.6 cm3 was 5% and 4%, respectively.
Conclusions—The observed risk of stroke or death after SRS was approximately 2% per year for the first 5 years after SRS,
declining to 0.2% annually for years 6 to 10. Patients with small volume BAVM may benefit from SRS compared with
the natural history of unruptured BAVM over the planned follow-up interval of the ARUBA trial (5–10 years). (Stroke.
2013;44:437-441.)
Key Words: arteriovenous malformation
■
hemorrhage
B
rain arteriovenous malformations (BAVM) are abnormal
blood vessel collections with an incidence of 1.12 to 1.34
per 100 000 person-years.1,2 Most BAVM are discovered after
an intracranial hemorrhage (ICH) with seizures and headaches being less frequent presentations. Whereas the treatment of patients with ruptured BAVM is typically directed
at eliminating the nidus to reduce the chance of rebleeding,
the best management of patients with unruptured BAVM is
controversial.3,4 The argument against treatment of patients
with unruptured BAVM is based on 3 factors. First, some
older studies may have overestimated the annual risk of ICH
for patients with unruptured BAVM.5 Second, the morbidity
associated with arteriovenous malformations (AVM) bleeding may be less than previously thought.6,7 Third, the risk of
neurological injury after treatment of unruptured BAVM may
be greater than previously described.8–10 A randomized trial
of unruptured brain arteriovenous malformations (ARUBA)
was designed to compare the risk of observation versus prophylactic intervention for patients diagnosed with unruptured
BAVM. The primary end points of the ARUBA trial are the
composite risk of death or stroke and risk of death or clinical
impairment, defined as a modified Rankin Score (MRS) ≥2.
Although the design of ARUBA has been criticized for a number of reasons, including the intended follow-up period after
■
stereotactic radiosurgery
■
stroke
randomization (planned, 5–10 years),11,12 it was funded by the
National Institute of Neurological Disorders (U01 NS051483)
and began enrolling patients in April 2007 at cerebrovascular
centers around the world. In this study, we analyzed the risk of
stroke or death and clinical impairment of patients having stereotactic radiosurgery (SRS) for unruptured BAVM using the
same eligibility criteria and primary end points as the ongoing
ARUBA trial.
Methods
Patients
All aspects of this retrospective study were approved by the Mayo
Clinic Institutional Review Board, Rochester, MN. To be eligible for
inclusion in the ARUBA trial and the current study, patients must have
an unruptured BAVM and be aged at least 18 years. Exclusion criteria
include: (1) evidence of recent or prior hemorrhage, (2) prior BAVM
treatment, (3) BAVM that are deemed untreatable, (4) MRS ≥2, (5)
life expectancy <10 years, (6) pregnancy, (7) thrombocytopenia,
(8) uncorrectable coagulopathy, (9) multiple BAVM, (10) previous
diagnosis of other intracranial vascular malformations, and (11) any
neurocutaneous syndromes.
Information on all patients having SRS at our center was entered
into a prospectively maintained database. BAVM morphology was
defined by size (largest dimension), volume, anatomic location,
and venous drainage. Location was defined as superficial (cerebral
hemisphere, cerebellum, corpus callosum) or deep (basal ganglia,
Received July 4, 2012; final version accepted November 16, 2012.
From the Departments of Neurological Surgery, Neurology, and Radiation Oncology, Mayo Clinic College of Medicine, Rochester, MN.
Correspondence to Bruce E. Pollock, MD, Department of Neurological Surgery, Mayo Clinic, Rochester, MN. E-mail [email protected]
© 2013 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.112.670232
437
438 Stroke February 2013
thalamus, or brain stem). BAVM were further classified based on
the Spetzler-Martin grading scale13 and the radiosurgery-based AVM
score (RBAS=[0.1][volume, cm3]+[0.02][age, years]+[0.5][location,
hemispheric/corpus callosum/cerebellar=0; basal ganglia/thalamus/
brain stem=1]).14
Table 1. Patient Characteristics
Stereotactic Radiosurgery and
Additional Procedures
Presentation
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Radiosurgery was performed using the Leksell Gamma Knife (Elekta
Instruments, Norcross, GA). Dose planning was based off a combination of either contrast-enhanced computed tomography or magnetic
resonance imaging (MRI) and stereotactic biplanar angiography.
One hundred sixty-two patients (93.1%) underwent single-session
SRS, whereas 12 patients (6.9%) underwent staged-volume AVM
procedures.15 The median treatment volume was 5.6 cm3 (interquartile range, 2.9–10.0). The median AVM margin dose was 18.0 Gy
(interquartile range, 18–20). Follow-up after radiosurgery consisted
of clinical examination and MRI at 1, 2, and 3 years after radiosurgery. Follow-up angiography was performed 3 to 5 years after SRS
to determine the status of the AVM. Patients with residual BAVM
on follow-up angiography were reevaluated for repeat radiosurgery
or surgical resection. Twenty-four patients (13.8%) underwent repeat
SRS and 7 patients (4.0%) underwent surgical resection. One patient
required placement of a ventriculoperitoneal shunt after an intraventricular hemorrhage caused hydrocephalus.
Follow-Up and Statistical Analysis
Follow-up after SRS was performed at either our institution or by
local physicians with imaging sent for independent review. A stroke
after SRS was defined as a new focal neurological deficit (FND),
seizure, or headache that was associated with an ICH or infarction
identified on computed tomography or MRI. Clinical impairment was
defined as a MRS ≥2 at the last follow-up examination. The risk of
stroke or death and clinical impairment were determined using the
Kaplan–Meier method. Univariate testing (log rank test) was performed on the following variables: sex, patient age, location (superficial versus deep), location (eloquent versus noneloquent), size (<3
cm versus ≥3 cm), volume, venous drainage (superficial versus any
deep), Spetzler–Martin grade, and RBAS. Multivariate testing was
performed on the patient and BAVM variables using a Cox proportional hazards model. We excluded the Spetzler–Martin grade and
RBAS from multivariate testing because of the redundant variables
(size, volume) and high concordance between these classification
systems. Statistical significance was determined by a P<0.05.
Results
Review of our prospectively maintained database found 185
ARUBA-eligible patients having SRS from 1990 to 2005.
In accordance with Minnesota state statutes, living patients
were required to consent to review of their medical records; 4
patients (2.3%) refused research authorization. Eight patients
(4.3%) had no clinical or radiological follow-up. The characteristics of the remaining 174 patients are shown in Table 1.
The median follow-up after SRS was 64 months (interquartile
range, 36–120). Forty-four patients (25.3%) had ≥10 years of
follow-up after SRS.
One hundred fifteen of 165 patients (69.7%) with ≥2 years of
follow-up had BAVM obliteration confirmed after initial SRS by
angiography (n=86) or MRI (n=29). Fifteen patients had BAVM
obliteration confirmed (angiography, n=8; MRI, n=7) after additional BAVM treatment for an overall obliteration rate of 78.9%.
The median time to obliteration after patients’ first SRS procedure was 40 months (range, 12–90). Fifteen patients (8.6%) had
a hemorrhagic stroke at a median of 21 months (range, 7–70)
after SRS. No patient had an ischemic stroke after SRS. Six
Factor
Men
Median age (IQR)
80 (45.9%)
42.5 years (33–50)
Seizure
70 (40.2%)
Headache
77 (44.3%)
Incidental
27 (15.5%)
BAVM location
Lobar
151 (86.8%)
Cerebellum
8 (4.6%)
Corpus callosum
5 (2.9%)
Basal ganglia
4 (2.3%)
Thalamus
4 (2.3%)
Brain stem
2 (1.1%)
Eloquent BAVM location*
Yes
126 (72.4%)
No
48 (27.6%)
Deep BAVM location†
Yes
10 (5.7%)
No
164 (94.3%)
Maximum BAVM diameter
<3 cm
101 (58.1%)
3–6 cm
72 (41.4%)
>6 cm
1 (0.6%)
Median maximum BAVM diameter (IQR)
27 mm (21–35)
Median BAVM volume (IQR)
5.6 cm3 (2.9–10.0)
Venous drainage
Superficial
100 (57.5%)
Any deep
74 (42.5%)
Spetzler–Martin grade
I–II
85 (48.9%)
III
55 (31.6%)
IV–V
34 (19.5%)
Median RBAS (IQR)‡
1.46 (1.13–1.92)
BAVM indicates brain arteriovenous malformation; IQR, interquartile range;
and RBAS, radiosurgery-based arteriovenous malformation score.
*According to the criteria of the Spetzler–Martin grading system.13
†Deep BAVM location included the basal ganglia, thalamus, or brain stem.
‡The RBAS was calculated according to the criteria of Pollock and Flickinger.14
patients (3.5%) had FND and 4 patients died (2.3%). The risk of
stroke or death was 10.3% at 5 years and 11.5% at 10 years after
SRS (Figure 1). Univariate analysis found BAVM size >3 cm
(P=0.02), increasing BAVM volume (P=0.001) and higher
RBAS (P<0.001) were associated with stroke or death after SRS
(Table 2). Multivariate testing found increasing BAVM volume
predictive of stroke or death after SRS (hazard ratio=1.06; 95%
confidence interval, 1.0–1.11; P=0.04; Figure 2).
Twelve additional patients (6.9%) had a FND from either
radiation-related complications (n=7) or subsequent resection
(n=5). Combined with the morbidity of post-SRS bleeding, 16
patients (9.2%) progressed to an MRS ≥2 at last follow-up.
Specifically, 11 of 86 patients (12.8%) with a pre-SRS MRS of
Pollock et al SRS for ARUBA-Eligible Patients 439
51% (2% annual risk) to 76% (4% annual risk). Over this
same time frame, studies on the microsurgical resection of
BAVM showed low morbidity rates for patients with small,
hemispheric BAVM.13,18 Taken together, this information led
neurological surgeons to believe that the majority of patients
with an unruptured BAVM should be treated to reduce the
future risk of ICH. As stated by Heros and Tu, “since the
natural history of AVMs, whether ruptured or unruptured, is
relatively poor, and since with careful selection many of these
lesions can presently be excised with acceptable morbidity,
surgical consideration should be given individually to every
patient with an AVM.”19 In general, this has been standard
neurosurgical teaching for the past 25 years,20 although the
indications for resection of unruptured BAVMs has been
questioned because of the chance of functional decline when
outcomes are assessed using more sensitive measures, such
as the MRS.9 Moreover, some recent natural history data
suggest that the annual risk of ICH may be as low as 1% for
patients with unruptured BAVM.21,22 Applying a 1% annual
hemorrhage rate to our hypothetical patient aged 45 years, the
lifetime risk of BAVM rupture decreases to 30%. If the chance
of serious morbidity or mortality after a BAVM hemorrhage is
in the range of 27% to 40%,6,7 then the lifetime risk of death
or significant clinical impairment would be approximately
10%. Therefore, to provide clinical benefit for patients with
unruptured BAVM, if such low long-term hemorrhage rates
are correct, the risk of BAVM treatment must be less than the
natural history of these lesions to justify intervention.
Stereotactic radiosurgery is an accepted treatment option
for patients with BAVM. Similar to microsurgery, the primary
goal of SRS is BAVM elimination to reduce the chance of
future hemorrhage. However, unlike BAVM resection that
eliminates the risk of bleeding at the time of surgery, SRS
results in nidus obliteration typically between 1 and 5 years
after the procedure. Initially, it was believed that there was an
increased risk of ICH after SRS prior to obliteration, but more
detailed analysis of this question has suggested that the risk of
bleeding is either unchanged or decreased after BAVM SRS.23–
26
Maruyama et al25 reviewed 500 BAVM patients having SRS
Figure 1. The actuarial risk of stroke or death after stereotactic
radiosurgery (SRS) (dashed lines, 95% confidence intervals).
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0 had a decline in their MRS (MRS 1=6; MRS 2=3; MRS 5=1;
MRS 6=1), and 11 of 88 patients (12.5%) with a pre-SRS MRS
of 1 had a decline in their MRS (MRS 2=4; MRS 3=2; MRS
4=1; MRS 6=4). Of note, 16 patients (18.2%) who presented
with seizures and had a pre-SRS MRS of 1 became seizurefree off medications after SRS, thereby improving to a MRS
of 0. The risk of progression to MRS ≥2 at last follow-up was
8.4% at 5 years and 12.0% at 10 years (Figure 3). Univariate
analysis found BAVM size >3 cm (P=0.02), increasing BAVM
volume (P=0.003), and higher RBAS (P=0.002) were associated with an increased risk of clinical impairment (Table 2).
Multivariate testing found increasing BAVM volume predictive of progression to MRS ≥2 after SRS (hazard ratio=1.06;
95% confidence interval, 1.01–1.09; P=0.01; Figure 4).
Discussion
Although interventional therapy for patients with unruptured
BAVM may provide benefit with regard to headache or
epilepsy, the primary rationale for treatment is to reduce the
future risk of ICH. A number of BAVM natural history studies
were published from 1980 to 1990 that showed an annual
hemorrhage risk of approximately 2% to 4%.5,16,17 Based
on these values, a patient discovered to have an unruptured
BAVM at the age of 45 (life expectancy of 35 years) would
have a subsequent hemorrhagic stroke risk ranging from
Table 2. Analysis of Factors Associated With Stroke/Death or Progression to MRS ≥2 After SRS
Progression to MRS ≥2
Stroke or Death
Factor
Univariate
HR (95% CI, P-Value)
Multivariate
HR (95% CI, P-Value)
Univariate
HR (95% CI, P-Value)
Multivariate
HR (95% CI, P-Value)
Sex
1.7 (0.6–5.0, 0.33)
2.3 (0.7–7.3, 0.16)
2.3 (0.7–7.1, 0.16)
2.8 (0.9–8.6, 0.09)
Age
1.03 (0.98–1.07, 0.13)
1.03 (0.99–1.07, 0.15)
1.03 (0.99–1.07, 0.12)
1.03 (0.99–1.07, 0.19)
Presentation (Seizure vs other)
1.3 (0.5–3.8, 0.62)
1.4 (0.5–4.3, 0.54)
1.08 (0.4–3.0, 0.89)
1.3 (0.5–4.0, 0.59)
Size (≤3 cm vs >3 cm)
3.8 (1.2–12.0, 0.02)
1.9 (0.5–7.6, 0.34)
3.3 (1.2–8.8, 0.02)
1.5 (0.4–5.4, 0.53)
BAVM location (superficial vs deep)
2.7 (0.6–11.9, 0.19)
3.3 (0.6–17.0, 0.16)
1.2 (0.2–8.9, 0.88)
1.2 (0.2–9.7, 0.85)
BAVM location (eloquent vs noneloquent)
BAVM volume
1.6 (0.5–5.6, 0.47)
1.08 (1.04–1.12, 0.001)
1.08 (0.3–4.6, 0.92)
2.8 (0.6–12.2, 0.18)
2.7 (0.5–13.5, 0.23)
1.06 (1.0–1.11, 0.04)
1.06 (1.02–1.1, 0.003)
1.06 (1.01–1.09, 0.01)
1.05 (0.4–3.0, 0.92)
Venous drainage (superficial vs any deep)
1.2 (0.4–3.3, 0.76)
1.2 (0.4–3.7, 0.70)
1.03 (0.3–2.6, 0.96)
Spetzler–Martin grade
1.6 (0.9–2.8, 0.10)
NT
1.6 (0.9–2.8, 0.06)
NT
RBAS
2.1 (1.5–2.9, <0.001)
NT
1.8 (1.3–2.6, 0.002)
NT
BAVM indicates brain arteriovenous malformation; CI, confidence interval; HR, hazard ratio; MRS, modified Rankin Score; NT, not tested; and RBAS, radiosurgerybased arteriovenous malformation score.
440 Stroke February 2013
Figure 2. The actuarial risk of stroke or death after stereotactic
radiosurgery (SRS) stratified by brain arteriovenous malformation
(BAVM) volume (solid line, ≤5.6 cm3; dashed line, >5.6 cm3).
Downloaded from http://stroke.ahajournals.org/ by guest on June 15, 2017
and reported an overall 54% reduction in the bleeding risk during the latency interval before nidus obliteration. Of note, the
risk reduction was greater for the 310 patients who presented
with ICH compared with the 190 patients without prior ICH.
Karlsson et al24 found some degree of protection against ICH
occurred as early as 6 months after SRS for patients receiving
a BAVM margin dose of 25 Gy. Included in all of these studies were patients with both ruptured and unruptured BAVM.
One of the primary objections to the ARUBA trial is that the
follow-up period is insufficient and, consequently, the complication rate of interventional therapy will surpass the natural
history bleeding rate.11,12 In the current series of unruptured
BAVM, we noted an annual ICH risk of approximately 2% for
the first 5 years after SRS, which declined to 0.2% per year for
years 6 to 10 after the procedure. Thus, the hemorrhage risk in
the first several years after SRS is comparable with the annual
bleed rate noted in natural history BAVM studies on patients
with unruptured BAVM (1.6%–2.2%),16,27 and then appears to
decrease below the risk for untreated BAVM as more patients
achieve nidus obliteration and are protected against the future
risk of bleeding.
In addition to the morbidity associated with BAVM bleeding, patients having SRS are also at risk for radiation-related
complications. Significant improvements in neuroimaging, dose-planning software, and SRS devices over the past
30 years have all contributed to improved patient outcomes
after BAVM SRS. Nonetheless, the parenchyma adjacent
to the BAVM receives a dose of ionizing radiation that can
result in tissue damage. The primary factors associated with
the amount of radiation delivered to nearby structures are the
BAVM volume and the prescribed radiation dose. Treatment of
larger BAVMs and higher prescribed doses both increase the
radiation exposure of the nearby tissues. Areas of increased
signal on long-repetition time MRI are noted in 30% to 50%
of patients after BAVM SRS. The imaging changes generally
occur in the first year after SRS, most are asymptomatic and
typically resolve on later MRI studies. Patients with BAVMs
involving the thalamus, basal ganglia, and brain stem are more
likely to develop FND secondary to the imaging changes noted
on MRI.28 Only 7 patients (4.0%) developed a permanent radiation-related FND after SRS, likely relating to both the size of
the treated BAVM (median, 5.6 cm3) and small number (5.8%)
of patients with BAVM in deep locations.
Figure 3. The actuarial rate of patients progressing to a modified Rankin Score (MRS) ≥2 after stereotactic radiosurgery (SRS)
(dashed lines, 95% confidence intervals).
Patient selection is a critical component of successful BAVM
SRS. The Spetzler–Martin grading scale is an accepted method
to predict outcomes after the surgical resection of BAVM,14 but is
less reliable in predicting obliteration and radiation-related complications after SRS. To that end, we developed a RBAS based on
3 patient factors (patient age, BAVM volume, BAVM location)
associated with not only nidus obliteration, but also radiationrelated complications.14 The RBAS has been validated by centers
performing Gamma Knife SRS, linear accelerator-based SRS,
and the CyberKnife SRS.29–31 In the current series, patients with
larger volume BAVM, and thus higher RBAS, were at greater
risk of stoke or clinical impairment after SRS. For example, the
10-year risk of MRS ≥2 for patients with a RBAS ≤1.50 was 2%,
compared with 13% at 5 years and 18% at 10 years for patients
with a RBAS >1.50. This means that younger patients with
small-volume unruptured BAVM had a very low risk of clinical
impairment or death after SRS, whereas older patients with larger
BAVM are more likely to suffer either a hemorrhagic stroke or
radiation-related complication after SRS. Consequently, this data
suggests that select patients with unruptured BAVM may benefit from SRS compared with medical management, even at the
follow-up period planned for the ARUBA trial.
A number of factors must be considered that limit the
results of this study. First, the study is a retrospective review
of patients selected to have SRS at our center, and therefore
it does not provide the quality of evidence derived from prospectively acquired population-based studies or randomized
Figure 4. The actuarial risk of patients progressing to a modified Rankin Score (MRS) ≥2 after stereotactic radiosurgery (SRS)
stratified by brain arteriovenous malformation (BAVM) volume
(solid line, ≤5.6 cm3; dashed line, >5.6 cm3).
Pollock et al SRS for ARUBA-Eligible Patients 441
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clinical trials. Second, there is no control group so comparing our results with previously published studies may not
accurately reflect the outcomes between randomized BAVM
patients having medical management or SRS. Third, although
BAVM obliteration after SRS was not the focus of this report,
the ARUBA trial requires angiography to confirm cure after
intervention, whereas we calculated our post-SRS obliteration
rate using both angiography and MRI. Fourth, our follow-up
period (median, 61.5 months) is similar to what is planned
for the ARUBA trial, but is not sufficient to evaluate the risk
of late radiation-related complications after BAVM SRS.32,33
Fifth, patients in our study underwent SRS from 1990 through
2005, and the ARUBA trial did not begin enrolling patients
until 2007. Although the patients in the present study were
not treated concurrently with the ARUBA trial, no significant
changes to our SRS technique or dose-prescription guidelines has occurred in recent years. The characteristics of 60
ARUBA-eligible patients having SRS at our center from
2007, until the present were comparable with the patients in
this study with regard to age, BAVM location, BAVM volume,
and radiation doses (data not shown). The crude annual risk of
ICH in 48 of these patients with follow-up after SRS (median,
22 months) was 2.9% (3 ICH/103.1 patient-years), which is
similar to the bleeding risk noted in our study group.
Disclosures
The authors have no financial or commercial disclosures. Bruce E.
Pollock is an adjudicator (Radiosurgery) for the ARUBA trial.
References
1. Al-Shahi R, Bhattacharya JJ, Currie DG, Papanastassiou V, Ritchie V,
Roberts RC, et al.; Scottish Intracranial Vascular Malformation Study
Collaborators. Prospective, population-based detection of intracranial
vascular malformations in adults: the Scottish Intracranial Vascular
Malformation Study (SIVMS). Stroke. 2003;34:1163–1169.
2. Stapf C, Mast H, Sciacca RR, Berenstein A, Nelson PK, Gobin YP, et al.
The New York Islands AVM Study. Design, study progress, and initial
results. Stroke. 2003;34:29–33.
3. Cockroft KM. Unruptured brain arteriovenous malformations should be
treated conservatively: no. Stroke. 2007;38:3310–3311.
4. Stapf C, Mohr JP. Unruptured brain arteriovenous malformations should
be treated conservatively: yes. Stroke. 2007;38:3308–3309.
5. Ondra SL, Troupp H, George ED, Schwab K. The natural history of
symptomatic arteriovenous malformations of the brain: a 24-year followup assessment. J Neurosurg. 1990;73:387–391.
6. Choi JH, Mast H, Sciacca RR, Hartmann A, Khaw AV, Mohr JP, et al.
Clinical outcome after first and recurrent hemorrhage in patients with
untreated brain arteriovenous malformation. Stroke. 2006;37:1243–1247.
7. van Beijnum J, Lovelock CE, Cordonnier C, Rothwell PM, Klijn CJ,
Al-Shahi Salman R; SIVMS Steering Committee and the Oxford
Vascular Study. Outcome after spontaneous and arteriovenous malformation-related intracerebral haemorrhage: population-based studies.
Brain. 2009;132(Pt 2):537–543.
8. Hartmann A, Stapf C, Hofmeister C, Mohr JP, Sciacca RR, Stein BM, et
al. Determinants of neurological outcome after surgery for brain arteriovenous malformation. Stroke. 2000;31:2361–2364.
9. Lawton MT, Du R, Tran MN, Achrol AS, McCulloch CE, Johnston
SC, et al. Effect of presenting hemorrhage on outcome after microsurgical resection of brain arteriovenous malformations. Neurosurgery.
2005;56:485–493; discussion 485.
10. Nowak-Sliwinska P, van Beijnum JR, Casini A, Nazarov AA, Wagnieres
G, van den Bergh H, et al. Organometallic ruthenium(II) arene compounds with antiangiogenic activity. J Med Chem. 2011;54:3895–3902.
11. Cockroft KM, Jayaraman MV, Amin-Hanjani S, Derdeyn CP, McDougall
CG, Wilson JA. A perfect storm: how a randomized trial of unruptured
brain arteriovenous malformations’ (ARUBA’s) trial design challenges
notions of external validity. Stroke. 2012;43:1979–1981.
12.Mathiesen T. Arguments against the proposed randomised trial
(ARUBA). Neuroradiology. 2008;50:469–471.
13. Spetzler RF, Martin NA. A proposed grading system for arteriovenous
malformations. J Neurosurg. 1986;65:476–483.
14.Pollock BE, Flickinger JC. Modification of the radiosurgery-based
arteriovenous malformation grading system. Neurosurgery. 2008;63:
239–243; discussion 243.
15. Pollock BE, Kline RW, Stafford SL, Foote RL, Schomberg PJ. The rationale and technique of staged-volume arteriovenous malformation radiosurgery. Int J Radiat Oncol Biol Phys. 2000;48:817–824.
16. Brown RD Jr, Wiebers DO, Forbes G, O’Fallon WM, Piepgras DG,
Marsh WR, et al. The natural history of unruptured intracranial arteriovenous malformations. J Neurosurg. 1988;68:352–357.
17.Graf CJ, Perret GE, Torner JC. Bleeding from cerebral arteriovenous malformations as part of their natural history. J Neurosurg.
1983;58:331–337.
18. Sisti MB, Kader A, Stein BM. Microsurgery for 67 intracranial arteriovenous malformations less than 3 cm in diameter. J Neurosurg.
1993;79:653–660.
19. Heros RC, Tu YK. Is surgical therapy needed for unruptured arteriovenous malformations? Neurology. 1987;37:279–286.
20. Ogilvy CS, Stieg PE, Awad I, Brown RD Jr, Kondziolka D, Rosenwasser
R, et al.; Special Writing Group of the Stroke Council, American Stroke
Association. AHA Scientific Statement: 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. Stroke. 2001;32:1458–1471.
21. Halim AX, Johnston SC, Singh V, McCulloch CE, Bennett JP, Achrol
AS, et al. Longitudinal risk of intracranial hemorrhage in patients with
arteriovenous malformation of the brain within a defined population.
Stroke. 2004;35:1697–1702.
22. Stapf C, Mast H, Sciacca RR, Choi JH, Khaw AV, Connolly ES, et al.
Predictors of hemorrhage in patients with untreated brain arteriovenous
malformation. Neurology. 2006;66:1350–1355.
23. Friedman WA, Blatt DL, Bova FJ, Buatti JM, Mendenhall WM, Kubilis
PS. The risk of hemorrhage after radiosurgery for arteriovenous malformations. J Neurosurg. 1996;84:912–919.
24. Karlsson B, Lax I, Söderman M. Risk for hemorrhage during the 2-year
latency period following gamma knife radiosurgery for arteriovenous
malformations. Int J Radiat Oncol Biol Phys. 2001;49:1045–1051.
25. Maruyama K, Kawahara N, Shin M, Tago M, Kishimoto J, Kurita H,
et al. The risk of hemorrhage after radiosurgery for cerebral arteriovenous malformations. N Engl J Med. 2005;352:146–153.
26. Pollock BE, Flickinger JC, Lunsford LD, Bissonette DJ, Kondziolka D.
Hemorrhage risk after stereotactic radiosurgery of cerebral arteriovenous
malformations. Neurosurgery. 1996;38:652–659; discussion 659.
27. Hernesniemi JA, Dashti R, Juvela S, Väärt K, Niemelä M, Laakso A.
Natural history of brain arteriovenous malformations: a long-term
follow-up study of risk of hemorrhage in 238 patients. Neurosurgery.
2008;63:823–829; discussion 829.
28. Flickinger JC, Kondziolka D, Lunsford LD, Kassam A, Phuong LK,
Liscak R, et al. Development of a model to predict permanent symptomatic postradiosurgery injury for arteriovenous malformation patients.
Arteriovenous Malformation Radiosurgery Study Group. Int J Radiat
Oncol Biol Phys. 2000;46:1143–1148.
29. Andrade-Souza YM, Zadeh G, Ramani M, Scora D, Tsao MN, Schwartz
ML. Testing the radiosurgery-based arteriovenous malformation score
and the modified Spetzler-Martin grading system to predict radiosurgical
outcome. J Neurosurg. 2005;103:642–648.
30. Colombo F, Cavedon C, Casentini L, Francescon P, Causin F, Pinna V.
Early results of CyberKnife radiosurgery for arteriovenous malformations. J Neurosurg. 2009;111:807–819.
31. Raffa SJ, Chi YY, Bova FJ, Friedman WA. Validation of the radiosurgery-based arteriovenous malformation score in a large linear accelerator
radiosurgery experience. J Neurosurg. 2009;111:832–839.
32. Pollock BE, Brown RD Jr. Management of cysts arising after radiosurgery to treat intracranial arteriovenous malformations. Neurosurgery.
2001;49:259–264; discussion 264.
33. Yamamoto M, Jimbo M, Hara M, Saito I, Mori K. Gamma knife radiosurgery for arteriovenous malformations: long-term follow-up results
focusing on complications occurring more than 5 years after irradiation.
Neurosurgery. 1996;38:906–914.
The Risk of Stroke or Clinical Impairment After Stereotactic Radiosurgery for
ARUBA-Eligible Patients
Bruce E. Pollock, Michael J. Link and Robert D. Brown
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Stroke. 2013;44:437-441; originally published online January 3, 2013;
doi: 10.1161/STROKEAHA.112.670232
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