VASOSPASM

ENDOVASCULAR MANAGEMENT OF CEREBRAL VASOSPASM

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Marike Zwienenberg-Lee, M.D.
Department of Neurological Surgery,
University of California, Davis,
Davis, California
Jonathan Hartman, M.D.
Department of Radiology,
University of California, Davis,
Davis, California
Nancy Rudisill, M.S.N.
Department of Neurological Surgery,
University of California, Davis,
Davis, California
CEREBRAL VASOSPASM REMAINS a leading cause of death and disability in patients
with ruptured cerebral aneurysms. The development of endovascular intervention in
the past two decades has shown promising results in the treatment of vasospasm.
Endovascular techniques that have been used in humans include intra-arterial infusion
of vasorelaxants and direct mechanical dilation with transluminal balloon angioplasty.
This article reviews the current indications and role of endovascular therapy in the
management of cerebral vasospasm, its clinical significance, and potential future
therapies.
KEY WORDS: Cerebral vasospasm, Endovascular therapy, Transluminal balloon angioplasty, Papaverine
Neurosurgery 59:S3-139-S3-147, 2006 DOI: 10.1227/01.NEU.0000239252.07760.59 www.neurosurgery-online.com

Jan Paul Muizelaar, M.D., Ph.D.
Department of Neurological Surgery,
University of California, Davis,
Davis, California
Reprint requests:
Marike Zwienenberg-Lee, M.D.,
Department of Neurological Surgery,
University of California, Davis,
4860 Y Street, Suite 3740,
Sacramento, CA 95817.
E-mail: mzwien@ucdavis.edu
Received, September 17, 2004.
Accepted, May 3, 2006.
A
fter the initial effects of hemorrhage,
cerebral vasospasm remains the second
leading cause of death and disability in
patients with ruptured cerebral aneurysm. In
the International Cooperative Trial on the
Timing of Aneurysm Surgery, conducted in
the early 1980s, vasospasm permanently af-
fected 13.5% of the patients and accounted for
33% of all death and disability (42, 43). With
modern treatment, including administration
of nimodipine, magnesium, “triple H” ther-
apy, endovascular intervention, and im-
proved critical care, the number of patients
permanently affected by cerebral vasospasm
seems to be lower; the estimated proportion of
patients who are dead or disabled from vaso-
spasm ranges from 5 to 9% (11, 17, 71, 74, 76),
and vasospasm accounts for 12 to 17% of all
cases of death and disability after subarach-
noid hemorrhage (SAH). Nevertheless, this
number is still substantial, and efforts to pre-
vent this potentially devastating complication
continue.
Cerebral vasospasm is defined as the
delayed-onset narrowing of the cerebral arter-
ies occurring after SAH. Angiographic vaso-
spasm occurs in approximately 70% of pa-
tients with aneurysmal SAH (18), but clinical
manifestations (i.e., delayed ischemic neuro-
logical deficit [DIND]) occur in only 30 to 50%
of patients with angiographic vasospasm (28,
30). If clinical vasospasm is present, associated
angiographic vasospasm is usually severe
(77). Independent predictors of symptomatic
vasospasm include thick clot in the basal cis-
terns, early rise in middle cerebral artery
(MCA) flow velocity on transcranial Doppler,
a Glasgow Coma Scale score of less than 14 on
admission, and rupture of an anterior cerebral
(ACA) or internal carotid artery (ICA) aneu-
rysm (70).
Endovascular therapy is typically reserved
for the treatment of DIND that does not re-
spond to hyperdynamic therapy (triple H
therapy). However, the timing and clinical cri-
teria for the institution of endovascular ther-
apy are not well established. If DIND is
present and other causes, such as electrolyte
abnormalities, hydrocephalus, procedure-
related stroke, and seizures, are excluded and
the patient is not responding to aggressive
triple H therapy, most clinicians think that the
patient should be evaluated and, if possible,
treated with endovascular therapy within
hours of the onset of DIND. Previous reports
have shown that patients who are treated
early seem to have the largest benefit. In pa-
tients with lateralizing signs, detection of
DIND may not be difficult. However, patients
with midline aneurysms tend to present more
often with subtle mental status changes. In
these patients, we have previously defined a
drop of more than 2 points on the Glasgow
Coma Scale score as indicative of DIND (58).
The goal of endovascular therapy in the
management of cerebral vasospasm is the re-
establishment of adequate cerebral perfusion.
This can be accomplished by either pharma-
cological or mechanical dilatation. Endovas-
cular techniques that have been used in hu-
mans include intra-arterial infusion of
Papaverine (IAP), nimodipine, nicardipine, or

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ZWIENENBERG-LEE ET AL.
verapamil, and transluminal balloon angioplasty (TBA). In
addition, the endovascular management of cerebral aneu-
rysms by endosaccular placement of coils has facilitated pro-
cedures such as cisternal irrigation and clot lysis (36), proce-
dures that were successful in preventing vasospasm, but were
abandoned in surgical patients because of the hemorrhagic
complications related to craniotomy and surgical dissection
(26). This article reviews the current indications and role of
endovascular therapy in the management of cerebral vaso-
spasm and touches on potential future therapies.
INTRA-ARTERIAL INFUSION OF
VASOACTIVE AGENTS
Papaverine
Papaverine hydrochloride is the most common agent used
for pharmacological dilatation of vasospastic cerebral vessels.
Papaverine is a member of the benzylisoquinoline group of
alkaloids. It was originally prepared as a crude alkaloid de-
rivative of opium, but is now manufactured synthetically. It is
a potent, nonspecific, endothelium-independent smooth mus-
cle relaxant, which mainly produces diffuse dilatation of ar-
teries and arterioles, but is also capable of dilating veins (14,
15). Its exact mechanism of action is unknown. It is thought to
be related to inhibition of cyclic adenosine monophosphate
(cAMP) and cyclic guanosine 3,5 monophosphate (cGMP)
phosphodiesterase activity, which decreases cAMP and cGMP
turnover in the smooth muscle cell (9, 52, 55, 66, 69).
IAP is usually administered superselectively via a micro-
catheter positioned proximal to the spastic vessel. The typical
Papaverine concentration infused is 0.3% (300 mg Papaverine
in 100 ml of normal saline). This dose is usually administered
to the affected vessel or vascular territory for 20 to 30 minutes
(6, 52). In the anterior circulation, the microcatheter is placed
in the supraclinoid carotid artery above the origin of the
ophthalmic artery. This allows infusion in both the middle and
anterior cerebral circulations, with dilution kept to a mini-
mum. If the spasm is present predominantly in either the ACA
or middle cerebral artery (MCA), but not both, then superse-
lective catheterization is required to prevent flow through the
route of least resistance into the less affected territory. Infusion
with the catheter located proximally in the common carotid
artery can cause runoff to other vascular territories and can
limit the effectiveness on the distal spastic vessels. In the
posterior circulation, the catheter is placed immediately prox-
imal to the vessels affected by vasospasm. Infusion of the
distal vertebral (VA) or proximal basilar artery below the
origin of the anterior inferior cerebellar artery may be limited
because of diffusion into perforators supplying the lower
brainstem.
Although Papaverine can lead to immediate reversal of
angiographic vasospasm, its effect is usually transient, even
with prolonged infusion (12, 24, 27, 40, 41, 47, 48, 50, 59, 61,
73). In almost all patients, vasospasm recurs within 1 day after
infusion. This is probably attributable to the short half-life of
S3-140 | VOLUME 59 | NUMBER 5 | NOVEMBER SUPPLEMENT 2006
Papaverine in the circulation (45–60 min). However, multiple
daily treatments with IAP can be effective for distal refractory
vasospasm and can carry patients through the period of the
most severe spasm. In animal experiments, Papaverine has
been shown to be most effective in the first 3 days after the
onset of vasospasm, but the vessels have tended to become
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unresponsive in the chronic phase (i.e., 5–9 d after the onset of
vasospasm) (53, 82).
Clinical improvement with IAP infusion is modest, varying
between 25 and 52% in most series (Table 1). However, the
data come only from small consecutive case series, and IAP
has not been subjected to testing in randomized clinical trials.
Complications associated with IAP include raised intracra-
nial pressure (ICP), seizures, transient hemiparesis, mydriasis,
hypotension, cardiac dysfunction, and respiratory arrest (5, 10,
13, 44, 51, 79, 80). Infusion proximal to the ophthalmic artery
leads to mydriasis, which is usually transient, but permanent
visual impairment and monocular blindness have been re-
ported (12). In the posterior circulation, infusion may result in
cardiac dysfunction and respiratory arrest, probably as a re-
sult of depression of respiratory and cardiovascular centers in
the brainstem. The development of hypotension is dose re-
lated and associated with infusion into multiple territories and
higher infusion rates. The cause of neurological impairments,
such as hemiparesis and seizures, is poorly understood. Mi-
crocrystal formation of Papaverine in areas of low flow may
lead to the development of microemboli, which subsequently
lodge in the distal circulation (52), and Papaverine is known to
precipitate when in contact with contrast media or heparin-
containing solutions. Seizures may be attributable to a procon-
vulsant effect of Papaverine at high doses, although Papaver-
ine has been used in epilepsy research as an anticonvulsant
agent because of its inhibitory effects on adenosine uptake
(10). More recently, concern has also been raised about poten-
tial neurotoxic effects of IAP (78). However, this was based on
a small magnetic resonance imaging study (i.e., five patients
who presented with signal changes and neurological decline
after IAP).
Raised ICP was a significant problem in a recent series from
the University of Cincinnati (2). The authors reported on 50
patients treated with IAP for symptomatic cerebral vaso-
spasm. In 21 cases, IAP was prematurely terminated because
of a sustained increase of ICP, and five patients died as a result
of intractably high ICP. The authors did not note a significant
impact on outcome with IAP and found that TBA was more
effective and was associated with fewer complications. They
recommended against the use of IAP in patients with diffuse
bilateral vasospasm because of the likelihood of developing
elevated ICP, and they felt that IAP should be reserved for
selected cases, such as opening a vasospastic vessel for sub-
sequent TBA or treating vasospasm refractory to medical
management and not amenable to TBA for technical reasons.
Overall, the use of IAP as primary therapy is declining in most
institutions in the United States. IAP is now generally used for
adjunctive therapy or in selected cases with isolated distal
vessel vasospasm.
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 ENDOVASCULAR MANAGEMENT OF CEREBRAL VASOSPASM

TABLE 1. Efficacy of intra-arterial Papaverine administrationa

Series Study No. Angiographic Clinical Favorable
Treatment Complications
(ref. no.) design of patients improvement (%) improvement (%) outcome (%)
Kaku et al., Case series 10 IAP 91 80

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1992 (40)
Kassell et al., Case series 12 IAP 57 25
1992 (41)
Livingston et Case series IAP
al., 1993 (48)
Clouston et al., Case series 14 IAP 95 50 70 One permanent monocular
1995 (12) blindness, one ICA
dissection w/o
complications, one seizure
Terada et al., Case series 12 IAP 92 25 67 One seizure
1997 (79)
Polin et al., Case control 31 IAP No difference in outcome of patients treated with
1998 (68) IAP versus control
Katoh et al., Case series 4 IAP N/A 25 50 One hypertension
1999 (44)
10 Prophylactic N/A N/A 90 Five decreased LOC, 1
IAPb hypertension, one
hemiparesis, one
decerebrate posturing, all
transient
Firlik et al., Case series 15 IAP 78 26 N/A One worsening vasospasm,
1999 (27) one transient brainstem
depression, one seizure,
one hypotension
Morgan et al., Case series 85 (52 DIND) Prophylactic N/A N/A 76 Transient hemiparesis
2000 (56) IAPb ⫹ TBA 0.4%, seizures 2.2%,
(5 patients) respiratory arrest 7%
Andaluz et al,, Case series 50 IAP ⫹ TBA 87 26 28 20 elevated ICP, ICP-
2000 (2) (16 patients) related death 10%, one
transient hemiplegia, one
transient mydriasis, one
transient brainstem
depression, one aneurysm
perforation. No
complications from TBA
a
DIND, delayed ischemic neurological deficit; IAP, intra-arterial Papaverine administration; ICA, internal carotid artery; ICP, intracranial pressure; LOC, loss of
consciousness; TBA, transluminal balloon angioplasty.
b
These patients were treated with IAP before onset of clinical vasospasm

Intra-arterial Calcium Channel Blockers
Direct intra-arterial infusion of calcium channel blockers
has received renewed interest (Table 2) (3, 8, 25). In the past,
calcium channel blockers were thought to act by a direct effect
on the vascular smooth muscle cell via interaction with the
calcium-dependent process of muscle contraction. Clinical tri-
als were subsequently conducted with the intravenously and
orally administered calcium channel blockers nicardipine and
nimodipine (1, 34, 35, 63, 65, 75). Only with the latter was there
a modest improvement of outcome, but no angiographic re-
versal of vasospasm was shown, indicating that the drug was
effective through some mechanism other than smooth muscle
relaxation (65). Direct intra-arterial infusion of nimodipine
into the ICA was also tested around that time. Grotenhuis et
al. (33) reported on six patients with vasospasm who were
treated with intra-arterial nimodipine, but there was no effect
on vessel caliber, and no clinical improvement was seen.
In a recent study, 25 patients with symptomatic vasospasm
who were treated with infusion of nimodipine into the carotid
artery or VA were retrospectively reviewed (8). Seventy-two
percent of these patients were good-grade patients on admis-
sion (World Federation of Neurosurgical Societies Grade
I–III), and 56% had Fisher Grade III SAH (29). Standard treat-
ment included triple H therapy, but none of the patients were

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ZWIENENBERG-LEE ET AL.
TABLE 2. Efficacy of intra-arterial calcium channel blocker administration
Series Study No.
Treatment
(ref. no.) design of patients
Grotenhuis et al., 1984 (33) Case series 6 Nimodipine
Biondi et al., 2004 (8) Case series 25 Nimodipine
Feng et al., 2002 (25) Case series 29 Verapamil
Badjatia et al., 2004 (3) Case series 18 Nicardipine
treated with balloon angioplasty. Nimodipine was infused
into the symptomatic carotid artery unilaterally in 21 cases,
the bilateral carotid arteries in seven cases, and the VA in three
cases, with a dose of 1 to 3 mg per vessel. The patients also
received intravenous nimodipine at a rate of 2 mg/h, which
was continued to 21 days posthemorrhage in patients who
developed vasospasm. There were no apparent complications,
and clinical improvement was observed in 19 (76%) patients,
resulting in a good outcome in 17 of these 19 (89.5%; 68% of
total). After a follow-up period of 3 to 6 months, 18 (72%) out
of 25 patients had a favorable outcome. However, successful
dilatation of infused vessels occurred in only 13 (43%) out of
30 procedures, raising some question as to the cause-and-
effect relationship between drug and outcome.
Intra-arterial verapamil and nicardipine were also studied
in consecutive case series. In a study of 29 patients, verapamil
resulted in angiographic improvement in one-third of the
cases, with an average increase of vessel diameter by 44%, but
neurological improvement was noted in only five (29%) out of
17 cases in which verapamil was used as the sole treatment
(25). In a smaller series, intra-arterial administration of nicar-
dipine was somewhat more successful (3). Eighteen patients
were treated with 0.5 to 6 mg of nicardipine per vessel, with
angiographic dilatation seen in all vessel segments and neu-
rological improvement in 42% of patients. An advantage of
intra-arterial infusion of any of these drugs is that multiple
treatments can be given.
TRANSLUMINAL BALLOON ANGIOPLASTY
Although human studies have shown that TBA produces a
long-lasting dilatation of vasospastic vessels, the precise
mechanism of action of TBA is not well understood. Proposed
mechanisms include disruption and dysfunction of the
smooth muscle cells, the extracellular matrix of the vessel wall,
or the connections in the basement membrane between
smooth muscle cells and the extracellular matrix (39a, 48a,
82a). In general, TBA does not seem to cause major structural
damage to the vessel wall, unless high balloon pressures are
applied (46). TBA typically results in smooth muscle flatten-
ing, mild matrix interruption, endothelial flattening, or denu-
dation. Vasospastic and normal vessel segments do become
less responsive to both vasoconstrictors and vasodilators im-
mediately after TBA (49).
S3-142 | VOLUME 59 | NUMBER 5 | NOVEMBER SUPPLEMENT 2006
Angiographic Clinical Favorable
improvement improvement outcome Complications
(%) (%) (%)
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0 0 Not stated None
43 76 72 None
34 29 (5/17 procedures) Not stated None
100 42 Not stated None
Zubkov et al. were the first to report that TBA was effective in
humans, with excellent success in carefully selected patients with
large vessel spasm (83). In the two decades since that initial
description, advancements have been made in balloon and cath-
eter technologies, making this technique more widely applicable
and safer (4, 19–21, 23, 37–39, 45, 61, 62, 67). The original balloons
used were relatively stiff latex balloons, but soft, flow-guided
silicone balloons, which (at least in theory) reduce the risk of
catastrophic vessel rupture, became available in the late 1980s,
followed more recently by wire-guided balloons. Flow-guided
balloons tend to be less traumatic to the vessels, but may impose
difficulties navigating into the ACA or posterior cerebral arteries
because of acute vessel angulation or tortuosity. Over-the-wire
systems allow for easier navigation into vessels inaccessible by
flow-guided balloons, but they are associated with an increased
risk of vessel perforation and rupture (62). Compliant and non-
compliant over-the-wire balloons are available. Compliant bal-
loons are less traumatic to the vessel wall and more trackable
through tortuous vessels. However, the smallest diameter avail-
able at this time is approximately 3.5 to 4 mm, and is, therefore,
larger than even the largest the proximal ACA or MCA. This
may impose risk during balloon inflation in these vessels. The
noncompliant balloons may be more traumatic because of their
stiffness, but they come in smaller diameters (e.g., 2–2.25 mm)
and cannot be overinflated as easily. It should be noted that none
of the balloons currently in use for cerebral angioplasty are Food
and Drug Administration approved for this procedure, and all
are thus used “off label.”
For the procedure, the intracranial arteries are catheterized
superselectively, most commonly using a transfemoral approach.
Creation of a digital roadmap is essential to facilitate the proce-
dure by allowing balloon manipulation with a superimposed
image of the vessels being angioplastied. To prevent thrombo-
embolic complications, the patients are heparinized unless there
is an absolute contraindication to doing so. A clotting time of 2 to
3 times baseline, or generally greater than 300, is desirable before
catheterization of the intracranial vessels. The patients are usu-
ally placed under general anesthesia or, if intubated already, are
paralyzed and sedated to prevent patient movement, which may
increase the risk of complications such as vessel rupture. How-
ever, if anesthesia is unavailable in a timely fashion, angioplasty
can be performed with sedation only. In either case, care should
be taken to prevent a drop in blood pressure during use of
sedative medications or anesthetic agents because cerebral per-
www.neurosurgery-online.com

fusion pressure must be maintained. Vessels amenable to angio-
plasty include the supraclinoid ICA, the M1 and sometimes M2
segments of the MCA, the A1 and (less commonly) A2 segment
of the ACA, the intracranial segment of the VA, the basilar artery,
and the P1 and (less commonly) P2 segment of the posterior
cerebral artery (61). Angioplasty of the A1 segment remains
technically challenging, and treatment of this vessel is possible in
fewer than 10% of the patients because of its relatively small size
and acute angulation as it arises from the ICA bifurcation (7, 19,
32, 39). As Newell et al. (61) have pointed out, it is important to
attempt to treat patients with ACA spasm, particularly when the
contralateral ACA is hypoplastic. Neurological sequelae from
ACA infarcts can be significant and include lower-extremity
weakness, hypesthesia, personality changes, transcortical motor
aphasia, abulia, and bladder and bowel incontinence (16). An-
gioplasty of the supraclinoid carotid artery sometimes improves
flow into the ACA, but, in some cases, Papaverine may be
needed to at least transiently increase flow or to facilitate balloon
navigation into the vessel.
Initially, the use of TBA was limited to the treatment of pa-
tients with symptomatic vasospasm that had become refractory
to other treatment modalities, such as calcium channel blockers
and triple H therapy. In addition, it was thought that TBA should
not be performed in patients with low-density areas on com-
puted tomographic scans because of the risk of reperfusion hem-
orrhage (61). Further experience indicated that initially asymp-
tomatic vessels with a milder degree of vasospasm would often
develop severe spasm if left untreated. For this reason, and also
to maximize pial collateral flow, the practice at most institutions
is to treat all accessible vessels that exhibit angiographic vaso-
spasm during the first treatment session. Small- and medium-
sized low-density areas on computed tomographic scans may
improve after angioplasty of the vessels supplying the affected
territories, and, thus, these changes are not considered an abso-
lute contraindication for treatment with TBA (61). However, TBA
is not recommended in patients with large MCA strokes, unless
an M2 branch not supplying the infarcted area can be accessed.
In each patient, the risk of reperfusion hemorrhage versus the
possibility of salvaging territory at risk, but not yet infarcted,
should be balanced.
The clinical success rate of TBA is variable (Table 3). A
number of reasonably large consecutive case series evaluating
the efficacy of TBA are now present in the literature (7, 39, 61,
67, 72). The angiographic improvement with TBA seems to be
high, reaching 80 to 100% in most series. Clinical improvement
is less frequent, but it remains more common than with IAP,
and it ranges from 30 to 80%. Early treatment seems to be
associated with increased efficacy, as will be described later in
this article (see “Timing of Endovascular Intervention”). In the
largest series published to date, 109 patients with symptom-
atic vasospasm were treated with TBA (61). Forty-seven (44%)
of the patients improved within 72 hours after treatment, 31
(28%) remained unchanged, and 31 (28%) deteriorated.
These numbers seem to be confirmed in a meticulous prospec-
tive study on the prevention and treatment of vasospasm with
TBA (balloon prophylaxis of aneurysmal vasospasm study
NEUROSURGERY
ENDOVASCULAR MANAGEMENT OF CEREBRAL VASOSPASM
[BPAV]). Preliminary analysis of the available blinded BPAV
data (see below) revealed 29 patients in whom therapeutic an-
gioplasty had been performed (Table 3). Therapeutic angioplasty
was performed within 24 hours of the development of medical
refractory DIND. Out of all patients who developed DIND, 68%
required TBA. The number of patients requiring therapeutic TBA
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was much lower in the prophylactic TBA than in the control
group; respectively, 12 and 27% of patients underwent therapeu-
tic TBA (P ⬍ 0.025). A total of 102 vessel segments were subjected
to angioplasty. Angiographic improvement was noted in 97% of
cases, but clinical improvement was seen in only 38% of cases.
Transcranial Doppler velocities were lower after treatment in
80% of cases and elevated in 13%.
No randomized clinical studies are currently available that
assess the effect of TBA on outcome, nor is much known of the
long-term effects of TBA. Nevertheless, the effect of angio-
plasty in the setting of cerebral vasospasm has been found to
be lasting, and re-treatments are rarely needed. Furthermore,
the angioplastied vessels normalize in luminal diameter over
time based on follow-up angiography. Complications result-
ing from TBA for cerebral vasospasm are uncommon and
include vessel perforation, unprotected aneurysm rerupture,
branch occlusion, hemorrhagic infarction, and arterial dissec-
tion. Vessel rupture is reported in 4% of cases, usually with
catastrophic outcome, and rebleeding from unclipped aneu-
rysms is found in roughly 5% of cases (7, 21, 22, 67, 81).
Prophylactic TBA
Despite the success rate of TBA in treating symptomatic
vasospasm, substantial numbers of patients are left with se-
vere neurological deficits from vasospasm. Recent data from
animals, as well as observations in humans, have indicated
that the prophylactic treatment of vessels exposed to perivas-
cular or subarachnoid blood may be effective in preventing
vessels from undergoing subsequent vasospasm (54).
A pilot study investigating the effect of prophylactic TBA in
humans was conducted at our institution (57, 58). Patients
enrolled were those with the highest risk of developing cere-
bral vasospasm (i.e., Fisher Grade III SAH), and these patients
underwent ballooning after treatment of the ruptured aneu-
rysm, but within 3 days postrupture. A silicon flow-guided
balloon was used for the procedure. Target vessels for the
anterior circulation were the A1 segment of the ACAs, the M1
segment of the MCAs, and the supraclinoid segment of the
ICAs. The posterior circulation target vessels were the P1
segment of the PCAs, the basilar artery, and the dominant VA
intradural segment. Prophylactic TBA was considered satis-
factory when it could be performed in at least two of the three
parts of the intracranial circulation (right and/or left carotid
system and/or vertebrobasilar system) and included the
aneurysm-bearing part of the circulation.
A total of 18 patients were treated with prophylactic TBA in
the pilot phase (Table 3). None of the patients developed DIND.
Outcome analysis revealed a favorable outcome in 83% of pa-
tients (i.e., 12 patients with good recovery and three patients with
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TABLE 3. Efficacy of transluminal balloon angioplastya

Angiographic Clinical Favorable
Series Study No.
Treatment improvement improvement outcome Complications Note
(ref. no.) design of patients
(%) (%) (%)

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Higashida et al., Case series 13 TBA 100 77 69 One patient had 36 vessels treated
1989 (37) hemorrhagic infarct
24 hours later and
died.
Newell et al., Case series 10 TBA Not stated 80 80 Two out of 10 31 vessels treated
1989 (62) rebled from
unprotected
aneurysm 1 week
s/p TBA; one
patient had MCA
stroke: no source
of emboli.
Fujii et al., 1995 Case series 19 TBA 94 63 89 None stated 36 vessel segments
(31) dilated
Eskridge et al., Case series 50 TBA Not stated 61 Not stated Two (4%) died 170 vessel
1998 (19) immediately as a segments dilated
result of vessel
rupture.
Bejjani et al., Case series 31 TBA ⫹/⫺ Not stated 72 90 No complications 81 vessels dilated
1998 (7) Papaverine from the dilatation;
three (10%)
retroperitoneal/
inguinal
hematomas.
Polin et al., Case series 38 TBA ⫹/⫺ 82 29 53 None reported
2000 (67) Papaverine
Newell et al., Case series 109 TBA ⫹/⫺ Not stated 44 Not stated Not stated
2001 (61) Papaverine
Muizelaar et al., Case series 18 Prophylactic N/A N/A 83 One patient had
2001 (57) TBA vessel rupture.
Oskouian et al., Case series 12 TBA Not stated 50 58 None from
2002 (64) angioplasty
Murayama et al., Case series 10 TBA ⫹/⫺ 100 Not stated 70 None from
2003 (59) Papaverine angioplasty
BPAV study Case series 29 TBA 97 38 N/A One arterial
(2004) dissection
a
TBA, transluminal balloon angioplasty; MCA, middle cerebral artery; N/A, not available; BPAV, balloon prophylaxis of aneurysmal vasospasm study.

moderate disability). Three patients died, two of whom had
developed pulmonary complications and one who had a vessel
rupture during prophylactic TBA. The vessel rupture was caused
by unintended balloon entry and inflation in the posterior infe-
rior cerebellar artery caused by patient movement and resultant
roadmap misregistration. Subsequently, all patients were treated
while under general anesthesia, and no other complications as-
sociated with TBA were observed.
According to the same protocol, patients with Fisher Grade
III SAH are currently being randomized to balloon treatment
versus standard medical and endovascular management in
the National Institutes of Health-funded balloon prophylaxis
of aneurysmal vasospasm trial. This study is conducted in five
centers in the United States, one center in Canada, and one
center in the Netherlands. At the time of this writing, 151 out
of the 185 projected patients have been enrolled. The data
remain blinded to treatment effect, but adverse events related
to the endovascular procedures require unblinding and are
shown in Table 4 . Overall, 469 neurointerventional procedures
were performed in 132 patients. Balloon prophylaxis was per-
formed in 73 patients. A total of 415 vessel segments under-
went prophylactic ballooning: ICA (n ⫽ 124), MCA (n ⫽ 123),
ACA (n ⫽ 21), posterior cerebral artery (n ⫽ 50), posterior
communicating artery (n ⫽ 4), basilar artery (n ⫽ 48), and VA
(n ⫽ 45) segments. In all patients, we were able to balloon two
of three parts of the cerebral circulation. Five patients (7%) had

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TABLE 4. Complications of neurointerventional procedures in 132 patients enrolled in the balloon prophylaxis of aneurysmal vasospasm
trial
Complication rate/
Procedures Complications
procedure (%)
Cerebral angiogram 295 3 1
Coil 68 2 3
Therapeutic 33 1 3
angioplasty
Prophylactic 73 5 7
angioplasty
Total 469 11 2 585
complications directly related to the procedure under investi-
gation. In three patients (4%), balloon prophylaxis caused a
fatal vessel rupture. One patient had an uneventful vessel
perforation by a guide wire, and another patient developed
temporary vasospasm during the angiogram, but this tempo-
rary vasospasm resolved spontaneously. When taking into
consideration the number of vessel segments that received
ballooning, our complication rate is 1% per ballooned vessel.
TIMING OF ENDOVASCULAR
INTERVENTION
The timing of intervention is an important determinant of the
outcome after treatment of vasospasm and persistence of neurolog-
ical deficit. Early intervention seems crucial to successful treatment.
Newell et al. (60) have suggested that IAP performed within 6 to 12
hours after the onset of ischemic symptoms was beneficial, whereas
treatment initiated beyond that time interval was not. Similarly, for
TBA, treatment seems more effective when initiated early. In a
recent study by Rosenwasser et al. (72), 84 patients with clinical
vasospasm underwent endovascular treatment with TBA and/or
superselective IAP in cases of distal vasospasm. Fifty-one patients
were treated within 2 hours after onset of clinical symptoms, and 33
patients underwent treatment more than 2 hours (up to 17 h) after
neurological decline. In the first group, 90% of patients had angio-
graphic improvement, and 70% of patients sustained clinical im-
provement. In the second group, angiographic improvement was
very similar at 88%, but clinical improvement was only seen in 40%
of the patients. Thus, the time window may be even shorter than
was previously appreciated (45), supporting investigation into pro-
phylactic interventions for vasospasm (58). Moreover, prophylactic
treatment can be performed at a time that secondary insults are not
yet so important, as opposed to the period when patients are al-
ready in vasospasm and increasingly vulnerable to ischemic injury.
CONCLUSION
In the past two decades, the development of endovascular
intervention, together with aggressive intensive care unit man-
agement, has greatly assisted in the treatment of cerebral vaso-
spasm. TBA seems to be more effective than pharmacological
NEUROSURGERY
ENDOVASCULAR MANAGEMENT OF CEREBRAL VASOSPASM
Complication rate/
Vessels treated Complications
vessel (%)
Downloaded from https://academic.oup.com/neurosurgery/article/59/suppl_5/S3-139/2558508 by Universität Heidelberg user on 17 November 2020
68 2 3
102 1 1
415 5 1
7 2
treatment, and up to 80% of patients can be treated at a relatively
small risk. Interpretation of the available studies should be per-
formed with caution, however, because the body of published
work consists nearly exclusively of retrospective institutional
case series (i.e., Level III significance). Randomized clinical trials
are needed to assess outcomes after these interventions, although
in cases of TBA randomization, this may be difficult because of a
loss of clinical equipoise. On a cellular and molecular level, a
better understanding of the mechanism of action of TBA is re-
quired because this can potentially lead to the development of
treatment strategies that are less invasive. Clinically, definitive
criteria to evaluate and compare treatment paradigms are lack-
ing, and standards to assess the effectiveness of therapy in these
patients need to be developed (61). In summary, the framework
has been laid for improving the treatment of cerebral vasospasm,
and forward strides have been made in the endovascular treat-
ment of cerebral vasospasm. However, much work remains to be
done to eradicate the devastating complications of ruptured ce-
rebral aneurysm.
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