Microsurgery for ARUBA Trial (A Randomized Trial

of Unruptured Brain Arteriovenous Malformation)–Eligible

Unruptured Brain Arteriovenous Malformations
Johnny Wong, PhD; Alana Slomovic, BSc; George Ibrahim, PhD; Ivan Radovanovic, PhD;
Michael Tymianski, MD, PhD

Background and Purpose—The management of unruptured brain arteriovenous malformations (ubAVMs) remains
controversial despite ARUBA trial (A Randomized Trial of Unruptured Brain Arteriovenous Malformation), a controlled
trial that suggested superiority of conservative management over intervention. However, microsurgery occurred in only
14.9% of ARUBA intervention cases, raising concerns about the study’s generalizability. Our purpose was to evaluate
whether, in a larger ARUBA-eligible ubAVM population, microsurgery produces acceptable outcomes.
Methods—Demographic data, AVM characteristics, and treatment outcomes were evaluated in 155 ARUBA-eligible bAVMs
treated with microsurgery between 1994 and 2014. Outcomes were rates of early disabling deficits and permanent
disabling deficits with modified Rankin Scale score ≥3 or any permanent neurological deficits with modified Rankin
Scale score ≥1. Covariates associated with outcomes were determined by regression analysis.
Results—Of 977 AVM patients, 155 ARUBA-eligible patients had microsurgical resection (71.6% surgery only and 25.2%
with preoperative embolization). Mean follow-up was 36.1 months. Complete obliteration was achieved in 94.2% after
initial surgery and 98.1% on final angiography. Early disabling deficits and permanent disabling deficits occurred in
12.3% and 4.5%, respectively, whereas any permanent neurological deficit (modified Rankin Scale score ≥1) occurred
in 16.1%. Among ubAVM of Spetzler–Martin grades 1 and 2, complete obliteration occurred in 99.2%, with early
disabling deficits and permanent disabling deficits occurring in 9.3% and 3.4%, respectively. Major bleeding was the
only significant predictor of early disabling deficits on multivariate analysis (P<0.001).
Conclusions—Microsurgery in this cohort produced less disabling deficits than ARUBA with similar morbidity and AVM
obliteration as other cohort series. This disparity between our results and ARUBA suggests that future controlled trials
Downloaded from http://ahajournals.org by on July 7, 2020

should focus on the safety and efficacy of microsurgery with or without adjunctive embolization in carefully selected
ubAVM patients.   (Stroke. 2017;48:136-144. DOI: 10.1161/STROKEAHA.116.014660.)
Key Words: angiography ◼ arteriovenous malformations ◼ microsurgery ◼ radiosurgery ◼ regression analysis

U nruptured brain arteriovenous malformations (ubAVMs)

are thought to be associated with an annual risk of a brain
hemorrhage of 1% to 4%.1,2 Management has been based on the
perception that obliteration of ubAVMs is beneficial by elimi-
nating the risk of future hemorrhage. However, this is contro-
versial and more so after ARUBA trial (A Randomized Trial
of Unruptured Brain Arteriovenous Malformation).2 This trial
compared conservative management with interventional treat-
ment that included any one or more of microsurgery, emboli-
zation, or radiosurgery for ubAVMs.2 It attempted to evaluate
the balance between the natural history risk of hemorrhage
from ubAVMs against that inherent in intervention using any
of these treatment modalities. ARUBA was terminated early
by the National Institutes of Health because of the superior-
ity of medical management over interventional therapy.2 The
primary outcome (composite event of death and symptomatic
stroke) was identified in 10.1% of the conservative manage-
ment group when compared with 30.7% in the interventional
treatment group at a mean follow-up of 33 months. ARUBA,
therefore, validated the natural history of ubAVMs and seem-
ingly justified a shift to conservative management.
However, a major concern with ARUBA is the heteroge-
neity of interventional modalities used and the lack of con-
sistent treatment assignment criteria. Of the 114 patients in
the interventional group, only 14.9% (17 patients) received
microsurgery, either alone (5 patients) or in combination with
endovascular or radiosurgery. Because of the small surgical
cohort, it is unclear whether the overall conclusions of ARUBA
should be generalized to microsurgical treatment. One per-
spective is that microsurgery offers the benefit of immediate
cure, eliminating further life-time risk of hemorrhage, and may
be safely performed in properly selected cases.3,4 Adopting the

Received July 7, 2016; final revision received September 12, 2016; accepted October 7, 2016.
From the Division of Neurosurgery, Toronto Western Hospital, University Health Network, Ontario, Canada (J.W., A.S., G.I., I.R., M.T.) and Department
of Surgery, University of Toronto, Ontario, Canada (J.W., G.I., I.R., M.T.).
Correspondence to Michael Tymianski, MD, PhD, Division of Neurosurgery, Toronto Western Hospital, 4W-435, 399 Bathurst St, Toronto, Ontario M5T
2S8, Canada. E-mail mike.tymianski@uhn.ca
© 2016 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.116.014660

136
 Wong et al   Microsurgery for Unruptured Brain AVMs    137
overarching conclusion of ARUBA could, therefore, unneces-
sarily deprive certain ubAVM patients of a beneficial therapy.
Our purpose was to evaluate whether there exists a subset of
ARUBA-eligible patients selected by clinical judgment and
AVM characteristics that can be safely treated by microsurgi-
cal resection. A secondary goal was to identify any prognostic
factors for outcome in this patient cohort.
Methods
Data Collection
This study was approved by the Research Ethics Board at University
Health Network and was conducted in accordance with the institu-
tional ethics guidelines. The University of Toronto Brain AVM study
group database is a prospectively collected database containing demo-
graphic, clinical, and radiological information. To identify patients
with ubAVMs treated by microsurgical resection at Toronto Western
Hospital between 1994 and 2014, the database was interrogated using
the search terms: arteriovenous malformation and AVM. All patients
with an unruptured intracerebral AVM and treated with microsurgery
were included in the study. Exclusion criteria included evidence of
previous intracranial hemorrhage on computed tomography or mag-
netic resonance imaging, diagnosis of other vascular malformations
(eg, cavernous malformations, facial, or body AVM), or any treatment
without microsurgical resection of AVM. All AVM cases were diag-
nosed based on magnetic resonance imaging, computed tomography
angiogram, or digital subtraction angiography (DSA).
Management of each individual ubAVM was discussed at mul-
tidisciplinary conference, in which multimodality treatment strate-
gies, including microsurgery, embolization or radiosurgery alone, or
in combination, were considered. Suitability for microsurgery and
need for preoperative embolization were determined by multidis-
ciplinary consensus, based on Spetzler–Martin (SM) grade, AVM
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location, angioarchitecture, including the presence of high-risk
features, high-flow shunting, or associated aneurysms. Operations
were performed by 4 neurosurgeons. Postoperative DSA was per-
formed within the first week of resection to verify bAVM resection.
Clinical follow-up was performed at 6 weeks and 3 to 6 months post
hospital discharge and at annual intervals thereafter. The database
and clinical records were retrieved and analyzed retrospectively
by 2 individuals who were not directly involved in the care of the
patients (J.W. and A.S.).
Study Variables
Study variables included patient demographic data, clinical presenta-
tion (seizures, headaches, neurological deficits, bruits, or asymptom-
atic if not relevant to the AVM), AVM characteristics (SM grading
based on size, eloquence, deep venous drainage, as well as location,
and associated aneurysms), pre- and post-treatment functional out-
comes (modified Rankin Scale scores [mRS]), and treatment outcomes
(AVM obliteration rates and new neurological deficits). AVM oblit-
eration was confirmed by DSA. Neurological deficits were defined as
early disabling deficit (EDD) if mRS ≥3 within 7 days of surgery and
permanent disabling deficit (PDD) if mRS ≥3 at the last clinical fol-
low-up. Other complications were recorded, including major bleeding
(defined as >1000 mL intraoperative blood loss, or transfusion require-
ment for ≥2 U of whole or packed red cells5), postoperative hematomas
requiring evacuation, and wound infection. bAVM were dichotomized
into low grade (SM grades 1 and 2) and high grade (SM grades 3–5).
Statistical Analysis
Where stated, Fisher exact tests were used for categorical variables,
and 2-sided t tests for continuous variables. A univariate logistic
regression analysis was performed using the dichotomized outcome
variable as the dependent variable to determine whether covariates
were associated with the primary outcomes (permanent neurological
deficit, EDD, and PDD). Significant covariates on univariate analysis
(P<0.05) were entered into a multivariate logistic regression. Two-
and three-way interactions were tested. Analyses were performed
using R statistics software (version 3.2.1).
Results
Patient Demographics and AVM Characteristics
From 1994 to 2014, 977 bAVM patients were treated of which
528 were ubAVMs. Surgery occurred in 168 patients, but 10
patients were excluded because of inadequate data because
the surgeries were performed before their referral to our insti-
tution, whereas in 3 patients the surgery consisted only of a
decompressive craniectomy to treat complications of AVM
embolization, leaving 155 patients (Figure 1). Mean follow-
up was 36.1 months (range 1–238 months).
Baseline demographics, clinical presentation, and AVM
characteristics are presented in Tables 1 and 2. There were
88 females (57%) and 67 males (43%); mean age at presenta-
tion was 38.5 years (range 12–64 years), including 8 patients
aged <18 years. The most common clinical presentations
were symptomatic seizures (47.7%), focal neurological defi-
cits (8.4%), or asymptomatic/incidental radiological findings
(43.9%). Multiple AVMs occurred in 3 patients (1.9%). The
most common AVM locations were frontal (29.6%), parietal
(27.7%), and temporal (25.2%). SM grading was distributed
accordingly: 52 grade 1 (33.5%), 66 grade 2 (42.6%), 30
grade 3 (19.4%), and 7 grade 4 bAVMs (4.5%). No SM grade
5 bAVMs were resected in this series. Intracranial aneurysms
were present in 15.5% of patients.
Treatment and Outcomes
Treatment modalities, outcomes, and complications are
presented in Figure 2 and Table 3. Microsurgery alone was
performed in 107 cases (69%), and in combination with pre-
operative embolization in 39 cases (25%) and preoperative
irradiation in 2 cases (1.3%). By SM grades, microsurgical
resection alone was performed in 78% of patients in SM1 and
SM2, 46% in SM3, and 14% in SM4. By comparison, preoper-
ative embolization was used in 17% of SM1 and SM2 patients
and 72% of SM4. AVM obliteration was achieved in 94.1% of
patients on initial DSA and 98.1% on final DSA. Incomplete
AVM obliterations were treated with repeat microsurgery in 4
patients and postoperative radiosurgery in 2 patients. Reasons
for incomplete obliteration on final DSA were refusal for
DSA (1 patient), refusal for treatment (1 patient), and loss
to follow-up (1 patient). Postoperative mRS was unchanged
or improved in 79.4% of patients, and mRS increased by 1
in 18.7%. Neurological deficits of any kind at last follow-up
were present in 16.1% of patients, whereas EDD and PDD
rates were 11.6% and 4.5%, respectively. Median length of
admission was 5 days. Other complications included 19
patients with major bleeding, 6 patients with postoperative
hematomas requiring evacuation, and 2 wound infections.
When analyzed according to the SM grades, there were 118
patients with SM1 and SM2. Within this group, obliteration
rates on initial and final DSA were 96.6% and 99.1%, respec-
tively. EDD occurred in 9.3% and PDD in 3.4% of SM1 and
SM2 patients, whereas neurological deficits of any kind at
final follow-up were present in 10.2%. Median length of stay
 138  Stroke  January 2017
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was 4 days. By comparison, in SM3 and SM4 patients, EDD
rates were 20% and 28.6%, respectively, whereas PDD rates
were 10% and 0%, respectively. In summary, a greater propor-
tion of SM3 and SM4 patients had preoperative embolization,
longer length of stay, and higher EDD and PDD when com-
pared with SM1 and SM2.
Univariate and multivariate analyses were performed to
identify predictive factors for poor outcome. On univari-
ate analysis (Table 4), several covariates were significantly
associated with permanent neurological deficits (P<0.05):
high-grade AVM, eloquence, deep venous drainage, AVM-
associated aneurysms, surgery alone, and major bleeding.
On multivariate analysis, a significant interaction was seen
between surgery alone and major bleeding, indicating that an
adjunct procedure (embolization) in addition to surgical inter-
vention significantly reduced the effect of major bleeding. In
patients who underwent surgery alone, major bleeding was
the only significant independent predictor (P<0.001) of per-
manent neurological deficit. For EDD, both high-grade AVM
and major bleeding reached significance on univariate analy-
sis, but only major bleeding was significant on multivariate
(P<0.001). Similarly, major bleeding was the only significant
factor on univariate analysis for PDD.
Discussion
ARUBA is the only prospective randomized trial compar-
ing medical management with interventional treatment for
Figure 1. Flow chart demonstrating the break-
down of 979 patients identified in the arterio-
venous malformation (AVM) database to 155
surgical patients with unruptured brain AVM for
final analysis. ICH indicates intracerebral hem-
orrhage; IVH, intraventricular hemorrhage; and
SAH, subarachnoid hemorrhage.
unruptured bAVMs with a statistically significant morbid-
ity associated with interventional treatment.6,7 It reflects the
current management of ubAVMs internationally as 39 active
centers across 9 countries were involved. ARUBA provided
prospective information on the natural history of ubAVMs,
confirming that it is not benign because 10.1% of patients
suffered a symptomatic stroke or death within 33 months.
However, ARUBA was criticized because of its low enroll-
ment rate, small sample size, short follow-up, high rate of
adverse outcomes, under-representation of surgical treatment,
and lack of treatment stratification.8–22 Its primary outcome
after interventional treatment was higher than in previous
cohorts treated with microsurgery or radiosurgery23–29 with-
out a clear explanation. It combined 3 different interventions
into a single amorphous category and did not discriminate
which modality was harmful.21 ARUBA also assumed equi-
poise among all ubAVMs between medical and interventional
treatments,30 an assumption not shared by many physicians,
which may explain the small proportion of patients enrolled
(226/1740).10–15 By not enrolling patients, physicians have
potentially introduced bias, leading to the current quandary
that ARUBA tried to avoid. It raises questions about the gen-
eralizability of ARUBA data to individual ubAVM treatment.
AVMs are heterogeneous, with varying angioarchitecture,
anatomic locations, and natural history.13 UbAVMs consid-
ered low grade for treatment are not associated with a more
benign natural history. The risks of treatment are not homoge-
neous where treatment strategies depend on characteristics of
 Wong et al   Microsurgery for Unruptured Brain AVMs    139

Table 1.  Baseline Patient Characteristics for 155 Unruptured Table 2.  Baseline AVM Characteristics of the Surgical
Brain Arteriovenous Malformation Patients Treated Cohort, Including AVM Laterality, Location, Associated
With Microsurgery, Including Mean Follow-Up, Clinical Aneurysms, Overall, and Individual Components of SM Grading
Presentation, Past History, and Preoperative mRS
AVM Characteristics Total
Patient Characteristics Total
Single/multiple lesions (%)
No. of patients 155
 Single 152 (98.1)
Age, mean (SD), y 38.5
 Multiple 3 (1.9)
Female (%) 88 (56.8)
AVM side (% of total lesions=159)
Follow-up, mean, mo 36.1
 Right 84 (52.8)
Clinical presentation (%)
 Left 75 (47.2)
 Seizure 74 (47.7)
AVM location (% of total lesions=159)
 Neurological deficit 13 (8.4)
 Frontal 47 (29.6)
 Bruit 0 (0)
 Parietal 44 (27.7)
 Headache 45 (29)
 Temporal 40 (25.2)
 Asymptomatic 68 (43.9)
 Occipital 16 (10.1)
Past history (%)
 Insular 6 (3.8)
 Smoking 85 (54.8)
 Cerebellum/posterior fossa 5 (3.2)
 Stroke/TIA 13 (8.4)
 Periventricular 1 (0.6)
 Mild head injury 4 (2.6)
Aneurysms (%)
 HHT 7 (4.5)
 AVM associated 14 (9.0)
Preoperative mRS (%)
 Non-AVM associated 10 (6.5)
 0 7 (4.5)
SM grade (%)
 1 68 (43.9)
 1 52 (33.5)
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 2 77 (49.7)
 2 66 (42.6)
 3 3 (1.9)
 3 30 (19.4)
HHT indicates heriditary hemorrhagic telangiectasia; mRS, modified Rankin
 4 7 (4.5)
Scale (score); and TIA, transient ischemic attack.
 5 0 (0)
the lesion, availability of individual treatment modalities, and Size (%)
institutional expertise.10,12,17,31–34
 <3 cm 112 (72.3)
Several retrospective series have recently been published
on ubAVMs. The SIVMS (Scottish Intracranial Vascular  3–6 cm 43 (27.7)
Malformation Study) reported on ubAVMs comparing con-  >6 cm 0 (0)
servative management with intervention, which also found Eloquent location (%) 62 (40)
superiority in the conservative group for death or handicap at
Deep venous drainage (%) 42 (27.1)
4 years and focal neurological deficit or death at 12 years.1
AVM indicates arteriovenous malformation; and SM, Spetzler–Martin.
Both SIVMS and ARUBA cohorts had predominantly non-
surgical interventions and bAVM obliteration rates of 63%
to 71% were observed in SIVMS.16 In contrast, Bervini et
Of 74 ARUBA-eligible patients, 61 patients had received inter-
al35 presented a 25-year microsurgical series from Sydney, vention, which included surgical resection in 70.5% of patients
Australia, of 427 unruptured bAVMs patients, who were (with and without preoperative embolization), and radiosur-
stratified according to the Spetzler–Ponce class4: for class A gery in the remainder. The risk of stroke or death was 14.7%
(n=190), the rate of permanent neurological deficit with mRS in the entire intervention group when compared with 7.7% in
increase >1 was 1.6% (95% confidence interval, 0.3–4.8%); the conservative group, though surgery still had a lower risk
class B (n=107), 14.0% (95% confidence interval, 8.6– of stroke or death (11.6%) than the overall intervention group.
22.0%); and class C (n=44), 38.6% (95% confidence interval, Functional outcomes demonstrated no significant differences
25.7–53.4%).35,36 Subsequent sensitivity analyses on the same and complete obliteration of AVMs was achieved in 93% of
database by Korja et al37 showed no statistical difference to treated patients. Similarly, Nerva et al38 reviewed outcomes of
the combined classes A and B adverse outcome rate of 7.7% 105 unruptured bAVM patients, including a subgroup analysis
when nonoperated patients were assumed to have adverse out- of 61 ARUBA-eligible patients, on whom microsurgery was
comes. Outcomes in ARUBA-eligible patients at University of used in 61% of low-grade bAVM (SM1 and SM2) and 40%
California, San Francisco (UCSF) have also been reported.15 of high-grade AVM. Complete obliteration was achieved in
 140  Stroke  January 2017
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all patients. Persistent neurological deficits and mRS ≥3 were
found in 16% and 7%, respectively, of the ARUBA-eligible
cohort. In SM1 and SM2 patients, lower rates of persistent
deficits and mRS ≥3 (7% and 0%, respectively) were reported.
Interestingly, a recent multicenter retrospective radiosurgical
series from 7 international institutions in 509 ARUBA-eligible
patients39 (mean follow-up 86 months) showed an AVM obliter-
ation rate of 75%, with a postradiosurgery latency hemorrhage
rate of 0.9% per year. The adverse neurological outcome, per-
manent neurological morbidity, and mortality rates were 13%,
5%, and 4%, respectively, which were more favorable than the
primary outcome in ARUBA interventional group.
Our analysis of 155 consecutive ubAVM patients who were
generally eligible for ARUBA and treated with microsurgery
at a single multidisciplinary institution represents 29.3% of
the entire ubAVM cohort (528 patients) treated during the
same period. The analyzed cohort had similar patient char-
acteristics to ARUBA except for 8 patients aged <18 years
and 3 patients with initial mRS >2. The SM grade distribution
Figure 2. Distribution of functional out-
comes (mRS) for all SM grades (A and
B) and for Spetzler–Martin (SM) grades 1
and 2 (C and D) at the indicated assess-
ment intervals: initial assessment, 7
d postoperative and at last follow-up.
Green: mRS unchanged or improved;
orange: mRS ≤2 and worse than initial
assessment; red: mRS ≥3. mRS indicates
modified Rankin Scale (score).
was also similar with no SM grade 5 patients and the majority
(76%) were SM1 and SM2. Within this subset, microsurgical
resection alone was performed in 78% of cases, when com-
pared with 14% in SM4. In high-grade ubAVMs, preoperative
embolization and neurological deficits were more common,
median length of stay and follow-up were longer, and AVM
obliteration rates were also lower.
Outcomes from our series demonstrated a similar result
to the aforementioned surgical series.15,38,40 In our series, the
overall EDD and PDD (mRS≥3) rates were 12.3% and 4.5%,
respectively. Postoperative DSA confirmed complete resec-
tion in 98.1% of cases, accounting for the refusal of 1 patient
to undergo DSA and thus assuming persistence of AVM in
that individual. In contrast, the low-grade ubAVMs (SM1 and
SM2) in our series were associated with higher obliteration
rates (99.2%) and lower PDD (3.4%), which compares favor-
ably to the overall morbidity (2.2%) and complete oblitera-
tion rates (98.5%) presented in a recent systematic review of
microsurgery on low-grade AVMs by Potts et al.40 The mean
 Wong et al   Microsurgery for Unruptured Brain AVMs    141

Table 3.  Distribution of Treatment Modalities, Outcomes, and Complications When Stratified According to SM Grade
Overall, n=155 SM1, n=52 SM2, n=66 SM3, n=30 SM4, n=7 SM1 and SM2, n=118
Treatment modalities (%)
 Surgery only: single operation 107 (69.0) 47 (90.4) 45 (68.2) 14 (46.7) 1 (14.3) 92 (78.0)
 Surgery only: multiple operations 4 (2.6) 0 (0) 4 (6.1) 0 (0) 0 (0) 4 (3.4)
 Preoperative embolization+surgery 39 (25.2) 5 (9.6) 15 (22.7) 14 (46.7) 5 (71.4) 20 (16.9)
 Preoperative radiosurgery+surgery 2 (1.3) 0 (0) 1 (1.5) 1 (3.3) 0 (0) 1 (0.8)
 Surgery+postoperative radiosurgery 2 (1.3) 0 (0) 1 (1.5) 1 (3.3) 0 (0) 1 (0.8)
 Embolization+surgery+radiosurgery 1 (0.6) 0 (0) 0 (0) 0 (0) 1 (14.3) 0 (0)
Outcomes (%)
 Cure on initial postopeartive DSA* 146 (94.2) 51 (98.1) 63 (95.5) 27 (90.0) 5 (71.4) 114 (96.6)
 Cure on final postoperative DSA* 152 (98.1) 52 (100) 65 (98.5) 29 (96.7) 6 (85.7) 117 (99.2)
 Length of admission, mean, d 7.1 4.3 8.2 7.1 17.9 6.4
 Length of admission, median, d 5.0 3.5 5.0 5.5 13.0 4.0
 mRS same or better at last FU 123 (79.4) 45 (86.5) 48 (72.7) 26 (86.7) 3 (43.9) 93 (78.8)
 mRS worse at last FU 32 (20.6) 7 (13.5) 18 (27.3) 4 (13.3) 4 (57.1) 25 (21.2)
Complications (%)
 Early neurological deficit, within 7 d 47 (30.3) 11 (21.2) 18 (27.3) 13 (43.3) 5 (71.4) 29 (24.6)
 Early disabling deficit, mRS≥3 within 7 d 19 (12.3) 5 (9.6) 6 (9.1) 6 (20.0) 2 (28.6) 11 (9.3)
 Permanent neurological deficit, at last FU 25 (16.1) 2 (3.8) 10 (15.2) 9 (30.0) 4 (57.1) 12 (10.2)
 Permanent disabling deficit, mRS≥3 at last FU 7 (4.5) 0 (0) 4 (6.1) 3 (10.0) 0 (0) 4 (3.4)
 Postoperative hemorrhage 6 (3.9) 2 (3.8) 0 (0) 2 (6.7) 2 (28.6) 2 (1.7)
Treatment modalities consisted of microsurgery with or without adjuvant embolization or radiosurgery. Outcomes included radiological and clinical
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outcomes. DSA indicates digital subtraction angiography; FU, follow-up; mRS, modified Rankin Scale (score); and SM, Spetzler–Martin.
*DSA refused by 3 patients.

and median duration of follow-up in our series were 36.1 and
18 months, respectively, which is comparable to the mean
follow-up in ARUBA (33 months). The short duration of
follow-up in this series can be explained by our institutional
practice to discharge patients from further clinical follow-up
beyond 12 months postoperatively once curative resection is
confirmed by DSA.
In summary, the current series and other retrospective sur-
gical cohorts have demonstrated that microsurgical resection
can be performed safely and effectively in a subset of predom-
inantly low-grade ubAVMs (SM1 and SM2). By definition,
one can infer that such ubAVMs would not have >1 high-risk
feature: eloquence, size >3 cm, or deep venous drainage. To
identify specific prognostic factors and AVM features associ-
ated with treatment risk, univariate and multivariate analyses
were performed in this study. On the basis of logistic regres-
sion, the most consistent significant predictors of permanent
neurological deficit, EDD, and PDD on univariate analysis
were high-grade AVM and major bleeding. Individual com-
ponents of the SM grading, such as eloquence and deep drain-
age, were also significant predictors of permanent deficit on
univariate analysis but did not reach significance in multivari-
ate modeling. Major bleeding was the most significant pre-
dictive factor for permanent neurological deficit, EDD, and
PDD on multivariate analysis. Although the threshold defined
herein for major bleeding in surgical patients (>1000 mL of
blood loss, or transfusion requirement of ≥2 U of whole blood
or packed red cells)5 is arbitrary, this may be a surrogate mea-
sure of either high-risk features in bAVM specified or unspeci-
fied by the SM grade or the surgeon’s technical expertise. The
relevance of major bleeding as a significant predictor for poor
outcome may be applicable to the role of preoperative embo-
lization. Embolization may be used as an adjunct to reduce
intraoperative bleeding by addressing high-risk features, such
as an intranidal aneurysm, or to generally reduce flow through
the nidus preoperatively, or to control deep arterial feeders
which may be difficult to access surgically. However, risks of
embolization will vary depending on the treatment strategy.
Occasionally, embolization has been used for definitive cure,
with reported cure rates of 15% to 50% and higher morbidity
rates.11,14,20,40 In ARUBA, embolization alone constituted 26%
of cases, but the treatment strategy or specific agents were not
mentioned.11 Within the subset of low-grade AVMs, a review
of endovascular series using Onyx embolization demonstrated
morbidity and cure rates of 6.2% and 29.5%, respectively.40
Although there is no established treatment algorithm or
paradigm at our institution, consensus decision at the multi-
disciplinary conference would determine the most appropri-
ate modality of treatment for individual bAVMs. In general,
microsurgery would be recommended if the bAVM is acces-
sible and can be resected with minimal acceptable morbidity,
usually in the setting of SM1 and SM2 and possibly SM3.
 142  Stroke  January 2017

Table 4.  Univariate and Multivariate Analyses for Predictive Table 4.  Continued
Factors of Permanent Neurological Deficit, EDD, and PDD
OR (95% CI) Significance
OR (95% CI) Significance
  Major bleeding 7.56 (2.31–24.76) <0.001
Permanent neurological deficit
PDD
 Univariate analysis
 Univariate analysis
  SM grade (high grade vs low
4.78 (1.94–11.78) <0.001   SM grade (high grade vs low
grade) 2.51 (0.53–11.79) 0.24
grade)
  Eloquence 0.25 (0.10–0.62) 0.003
  Age 1.02 (0.96–1.08) 0.61
  Size of nidus 0.51 (0.21–1.25) 0.14
  AVM-associated aneurysms 1.73 (0.19–15.50) 0.62
  Venous drainage 0.27 (0.11–0.64) 0.003
  Nonassociated aneurysms 1.70 (0.001–∞) 0.99
  Age 0.98 (0.95–1.01) 0.19
  Major bleeding 6.19 (1.27–30.17) 0.02
  AVM-associated aneurysms 3.36 (1.02–11.06) 0.046
  Surgery alone 0.58 (0.13–2.71) 0.49
  Nonassociated aneurysms 0.56 (0.07–4.63) 0.59
  Cure on initial DSA 5.82 (0–∞) 0.99
  Major bleeding 6.75 (2.38–19.11) <0.001 Significant 2-way interaction between surgery alone and major bleeding
  Surgery alone 0.34 (0.14–0.82) 0.016 for PDD (P=0.002); separate models for surgery alone and other treatments.
AVM indicates arteriovenous malformation; CI, confidence interval; DSA, digital
  Cure on initial DSA 0.28 (0.06–1.26) 0.09 subtraction angiography; EDD, early disabling deficit; OR, odds ratio; PDD,
 Multivariate analysis* permanent disabling deficit; and SM, Spetzler–Martin.
*Models drawn on significant univariate variables (P<0.05).
  SM grade (high grade vs low
2.79 (1.00–7.81) 0.05
grade)
This can be observed in the distribution of SM grading in our
  AVM-associated aneurysms 2.48 (0.62–9.82) 0.19 cohort, with few SM4 or SM5 patients treated. Adjunctive
  Surgery alone 0.45 (0.17–1.22) 0.12 preoperative embolization may be used to aid microsurgical
  Major bleeding 3.82 (1.18–12.37) 0.025
resection by addressing high-risk features, such as intranidal
aneurysms, or major arteriovenous shunts, or the deep nidal
 Two-way interactions component of a multicompartment AVM, and is more com-
Downloaded from http://ahajournals.org by on July 7, 2020

  Surgery alone×Major
36.24 (3.58–367.21) 0.002
monly used in higher SM grades. For deeply located bAVM,
bleeding stereotactic radiosurgery may be recommended. In summary,
  Surgery alone, n=107 not all bAVM should be considered homogeneously for inter-
vention, and intervention should be individualized according
   SM grade 2.91 (0.55–15.43) 0.21
to the AVM characteristics and the expertise of the treating
   AVM-associated institution.
1.90 (0.26–13.79) 0.52
aneurysms
The current series highlights the need for continuing inves-
   Major bleeding 19.11 (3.42–106.55) <0.001 tigation into identifying prognostic factors to appropriately
  Other treatments, n=48 select ubAVM patients for treatment. Potts et al40 recently
proposed a new randomized trial for low-grade bAVM to ulti-
   SM grade 2.68 (0.67–10.34) 0.16
mately address concerns raised by ARUBA, BARBADOS trial
   AVM-associated (Beyond ARUBA: Randomized Low-Grade Brain AVM Study:
1.21 (0.11–13.80) 0.88
aneurysms Observation Versus Surgery). It is hoped that this would inspire
   Major bleeding 0.62 (0.10–3.94) 0.61 greater participation from neurosurgeons in high-volume centers
EDD to produce a positive result against ARUBA. However, similar
issues with funding and duration of follow-up may also apply
 Univariate analysis
to BARBADOS, as has plagued ARUBA previously. Given
  SM grade (high grade vs low the scarcity of AVMs and the complexity of their treatments,
2.98 (1.09–8.23) 0.035
grade) the cumulative experience from high-volume surgical centers
  Age 1.02 (0.98–1.05) 0.45 on bAVM,3 with this study included, will supply data to refine
  AVM-associated aneurysms 2.29 (0.57–9.15) 0.24 future prospective intervention trials for all ubAVMs, such that
an evidence-based treatment algorithm may be formulated.
  Nonassociated aneurysms 0.83 (0.10–7.02) 0.87
  Major bleeding 9.16 (3.00–27.96) <0.001 Limitations of Current Study
  Surgery alone 0.52 (0.19–1.40) 0.19 Although our data were collected prospectively, it remains
  Cure on initial DSA 0.37 (0.07–1.99) 0.25 a retrospective review from a single institution. Surgical
patients were selected mainly based on the SM grade, angioar-
 Multivariate analysis*
chitecture, and location of bAVM, and thus, low-grade lesions
  SM grade 0.17 (0.54–5.37) 0.36 were heavily represented. Outcomes were assessed by clini-
(Continued ) cians who were not blinded or independent of the care of the
 Wong et al   Microsurgery for Unruptured Brain AVMs    143
patients. Adjuvant endovascular techniques have evolved in
the past 20 years, the results, therefore, reflect past treatment
trends, rather than the latest techniques.17
Conclusions
Although ARUBA remains the only level 1 evidence for man-
agement of ubAVMs, our study demonstrates the safety of
microsurgical resection in a carefully selected population of
ubAVM patients based on SM grade, AVM angioarchitecture,
and judicious use of preoperative embolization. It adds weight
to the emerging evidence from other microsurgical series
consisting of predominantly low-grade ubAVMs (SM1 and
SM2) that microsurgery can be efficacious and challenges the
conclusion that medical management is superior to all inter-
ventions. Data from retrospective surgical series, such as this
study, may be used to develop future prospective trials and a
potential treatment algorithm for ubAVMs.
Acknowledgments
All authors contributed to the data collection, writing, statistical
analysis, and illustration of the article. Dr Tymianski is a Canada
Research Chair (tier 1) in translational stroke research.
Sources of Funding
This work was funded by the aneurysm research fund, Neurovascular
Therapeutics Program, University Health Network. Dr Wong was
supported by the Royal Australasian College of Surgeons for the
Stuart-Morson Travel Scholarship.
Disclosures
Downloaded from http://ahajournals.org by on July 7, 2020
None.
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