REVIEW ARTICLE


Endovascular Treatment
C O N T I N UU M A UD I O
of Acute Ischemic Stroke
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I NT E R V I E W A V AI L A B L E
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By Gisele S. Silva, MD, MPH, PhD; Raul G. Nogueira, MD

CITE AS:
CONTINUUM (MINNEAP MINN)
2020;26(2, CEREBROVASCULAR
DISEASE):310–331.
Address correspondence to
Dr Gisele S. Silva, Estado de Israel,
379 41, São Paulo, SP, Brazil,
giselesampaio@hotmail.com.
RELATIONSHIP DISCLOSURE:
Dr Silva has received
compensation for serving on
advisory boards for Bard
Pharmaceuticals Ltd and
Boehringer Ingelheim
International GmbH and for
serving on a speaker’s bureau for
Bayer AG, Boehringer Ingelheim
International GmbH, and Pfizer
Inc and has received research
support from the Ministry of
Health (Brazil) (02216643) and
Servier. Dr Nogueira has received
personal compensation for
serving as a principal investigator
for Cerenovus/Neuravi Ltd,
Imperative Care Inc, and Phenox,
Inc; on the physician advisory
board for Anaconda Biomed SL,
Genentech, Inc, and Prolong
Pharmaceuticals; and on a
steering committee for Biogen.
Dr Nogueira has received
grants/research support from
Koninklijke Philips NV, the
Ministry of Health (Brazil), and
Sensome and has held stock
options in Astrocyte
Pharmaceuticals Inc, Brainomix,
Ceretrieve Ltd, Corindus, Inc,
Vesalio, LLC, and Viz.ai, Inc.
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
Drs Nogueira and Silva report no
disclosure.
© 2020 American Academy
of Neurology.
ABSTRACT
PURPOSE OF REVIEW: This article reviews the actual indications for mechanical
thrombectomy in patients with acute ischemic stroke and how the
opportunities for endovascular therapy can be expanded by using the
concept of clinical-imaging or perfusion-imaging mismatch (as a surrogate
for salvageable tissue) rather than time of ischemia.
RECENT FINDINGS:Six randomized controlled trials undoubtedly confirmed
the benefits of using endovascular thrombectomy on the clinical outcome
of patients with stroke with large vessel occlusion within 6 hours from
symptom onset compared with those receiving only standard medical
care. In a meta-analysis of individual patient data, the number needed to
treat with endovascular thrombectomy to reduce disability by at least one
level on the modified Rankin Scale for one patient was 2.6. Recently, the
concept of “tissue window” versus time window has proved useful for
selecting patients for mechanical thrombectomy up to 24 hours from
symptom onset. The DAWN (DWI or CTP Assessment With Clinical
Mismatch in the Triage of Wake-Up and Late Presenting Strokes
Undergoing Neurointervention) trial included patients at a median of
12.5 hours from onset and showed the largest effect in functional outcome
ever described in any acute stroke treatment trial (35.5% increase in
functional independence). In DEFUSE 3 (Diffusion and Perfusion Imaging
Evaluation for Understanding Stroke Evolution 3), patients treated with
mechanical thrombectomy at a median of 11 hours after onset had a 28%
increase in functional independence and an additional 20% absolute
reduction in death or severe disability.
SUMMARY: For patients with acute ischemic stroke and a large vessel
occlusion in the proximal anterior circulation who can be treated within
6 hours of stroke symptom onset, mechanical thrombectomy with a
second-generation stent retriever or a catheter aspiration device should
be indicated regardless of whether the patient received treatment with
intravenous (IV) recombinant tissue plasminogen activator (rtPA) in
patients with limited signs of early ischemic changes on neuroimaging. Two
clinical trials completely disrupted the time window concept in acute
ischemic stroke, showing excellent clinical outcomes in patients treated
up to 24 hours from symptom onset. Time of ischemia is, on average, a
good biomarker for tissue viability; however, the window of opportunity
for treatment varies across different individuals because of a range of
compensatory mechanisms. Adjusting time to the adequacy of collateral

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flow leads to the concept of tissue window, a paradigm shift in stroke KEY POINTS
reperfusion therapy.
● Although IV recombinant
tissue plasminogen activator
(rtPA) is safe and effective
in reducing disability in
INTRODUCTION patients with acute ischemic

S
troke is a major cause of death worldwide.1,2 Fortunately, reperfusion stroke, several limitations
prevent its more widespread
therapies have changed the outcome of many patients with acute
use, including its narrow
ischemic stroke, preventing death and incapacity.3,4 Although therapeutic time window
intravenous (IV) recombinant tissue plasminogen activator (rtPA) is and poor effect in the
safe and effective in reducing disability in patients with acute ischemic recanalization of large
stroke, several limitations prevent its more widespread use, including its narrow vessels.

therapeutic time window and poor effect in the recanalization of large vessels.5,6 ● An essential premise in
Recently, endovascular therapy has been proven a safe and effective therapy for the development and
patients with large vessel occlusion who do not respond to or are ineligible for IV optimization of
thrombolysis. The pivotal clinical trials of mechanical thrombectomy for acute endovascular therapies for
acute ischemic stroke is the
ischemic stroke focused on a time window of up to 6 to 8 hours from symptom onset notion of the ischemic
and have used a broad range of neuroimaging modalities for patient selection.7–12 penumbra, essentially
More recently, the concept of “tissue window” versus time window has described as the area of
proved useful for selecting patients for mechanical thrombectomy up to 24 hours brain tissue that is still viable
but is critically
from symptom onset.13,14 An essential premise in the development and
hypoperfused and will
optimization of endovascular therapies for acute ischemic stroke is the notion of progress to infarct in the
ischemic penumbra, essentially described as the area of brain tissue that is still absence of timely
viable but is critically hypoperfused and will progress to infarct in the absence of reperfusion.
timely reperfusion (CASE 4-1).15,16 Even though the paradigm of “time is brain”
● The different behaviors
has been vital to strengthen the importance of rapid treatment in acute stroke, relative to the time–
several investigations have demonstrated that other factors contribute to the ischemia construct are now
degree of ischemic injury at any point in time.21,22 The different behaviors better delineated, allowing
relative to the time/ischemia construct are now better delineated, allowing for for the possibility of
improving the selection of
the possibility of improving the selection of patients for acute reperfusion patients for acute
therapies. This article reviews the indications and supporting evidence for reperfusion therapies.
endovascular therapy in acute ischemic stroke as well as how this treatment can
be offered to a greater number of patients after the linear concept of time of
ischemia has evolved into the tissue window paradigm.

DEFINING THE ISCHEMIC PENUMBRA

Following an intracranial large vessel occlusion, three zones of injury can be
identified: the ischemic core zone (tissue irreversibly injured even if blood flow is
reestablished), the ischemic penumbra (ischemic but still viable cerebral tissue
that is the main target of reperfusion therapy), and the zone of benign oligemia
(an area with a milder reduction in tissue perfusion that does not actually place
the tissue at risk) (FIGURE 4-3).22–24
In the ischemic core zone, blood flow less than 10% to 25% of the normal
cerebral blood flow with consequent loss of oxygen and glucose results in rapid
depletion of energy stores, leading to necrosis of neurons and glial cells. It is
estimated that 1.9 million neurons are lost during each minute of ischemia.21 The
duration of the penumbra in humans varies substantially, depending on factors
such as degree of collateral blood flow supply, cerebral perfusion pressure,
susceptibility of tissue to ischemia and ischemic preconditioning, location of the vessel
occlusion, and other specific factors such as hyperglycemia, body temperature, and

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ENDOVASCULAR TREATMENT OF ACUTE ISCHEMIC STROKE

oxygen delivery capacity (CASE 4-2).22,25,26 Nonetheless, cells in the penumbra area
will eventually die if perfusion is not reestablished because collateral circulation is
inadequate to maintain the neuronal demand for oxygen and glucose indefinitely.23,27
In patients with proximal cerebral artery occlusions, no single practical and
reliable imaging biomarker predicts infarct growth into the surrounding
penumbra; however, the principles of clinical-imaging mismatch and perfusion-
imaging mismatch have revolutionized the evaluation of patients with acute
ischemic stroke.15,22,28,29

UNDERSTANDING THE COLLATERAL CIRCULATION

Survival of brain tissue supplied by an occluded or very stenotic artery
depends on (1) the status of the obstruction (circulation may be restored
either spontaneously or by active treatment to dissolve or mechanically remove
the blockage); (2) in case of partial occlusions, the ability of the systemic
circulation to adequately supply the ischemic region through augmented flow
either spontaneously or through therapeutic interventions such as induced
hypertension; and (3) the presence and strength of collateral blood supply.23,30–32

CASE 4-1 A 50-year-old man with a history of hypertension and diabetes mellitus
had a sudden onset of dysarthria, left hemiplegia, hemineglect, and
sensory loss. His daughter witnessed the first symptoms, but as they live
in a rural area, he arrived at the hospital 11 hours after symptom onset.
His National Institutes of Health Stroke Scale score at hospital
admission was 17. His noncontrast head CT had an Alberta Stroke Program
Early CT Score (ASPECTS) of 6 (hypodensities at the caudate, lentiform
nucleus, insula, and internal capsule). CT angiography confirmed a
right middle cerebral artery occlusion with excellent collateral flow
(score of 3 in the Souza collateral grading system) (FIGURE 4-1).17–20 His core
ischemic lesion was 18 mL (cerebral blood flow, less than 30%), and his
hypoperfused area was 201 mL (mismatch ratio, 11.2). He was
successfully treated with mechanical thrombectomy (modified
thrombolysis in cerebral infarction [TICI] score, 3) (FIGURE 4-2). His
modified Rankin Scale score at discharge was 2 (mild left hemiparesis,
4/5 muscle strength).

COMMENT This case illustrates the notion of the ischemic penumbra. Even in a late
time window (11 hours after symptom onset), based on the presence of
salvageable tissue determined by the use of advanced neuroimaging, this
patient was successfully treated with mechanical thrombectomy.

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 The cerebral collateral circulation constitutes an adjuvant chain of vascular
pathways that sometimes preserve cerebral perfusion when the primary vessel
supplying the region in question becomes occluded.33 Hypoperfusion due to
hemodynamic failure, thrombotic or embolic events, or a combination of these
factors may result in the recruitment of collaterals.34 Recruitment of collateral
circulation possibly relies on the chronological course of several compensatory
metabolic, hemodynamic, and neural responses. The persistence of these
protective vascular channels may influence the severity of the ischemic injury.33,35,36
Collateral circulation comprises extracranial sources of cerebral blood flow and
intracranial pathways of ancillary perfusion. Cerebral collaterals can be broadly
divided into the short bypass segments at the circle of Willis and the elongated
leptomeningeal anastomotic routes able to deliver retrograde perfusion to adjacent
vascular territories. The term primary collaterals refers to the circle of Willis, secondary
collaterals to the ophthalmic and leptomeningeal arteries, and tertiary collaterals to
newly developed vessels through angiogenesis.33,36
Blood flow through the anterior communicating artery and reversal of flow in
the proximal anterior cerebral artery can provide collateral support in the

FIGURE 4-1
Imaging showing noncontrast head CT (A) with an Alberta Stroke Program Early CT Score
(ASPECTS) of 6, CT angiogram (B) confirming a right middle cerebral artery occlusion with
excellent collateral flow (score 3), and an automated perfusion evaluation (C) depicting a
mismatch ratio of 11.2 (core ischemic lesion of 18 mL and hypoperfused area of 201 mL). CONTINUED ON
CBF = cerebral blood flow; Tmax = time to maximum. PAGE 314

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ENDOVASCULAR TREATMENT OF ACUTE ISCHEMIC STROKE

CONTINUED FROM
PAGE 313

FIGURE 4-2
Modified thrombolysis in cerebral infarction (mTICI) score with 2c grading scale criteria.
AP = anteroposterior; LAT = lateral.

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 KEY POINTS

● The duration of the

penumbra in humans varies
substantially, depending on
factors such as degree of
collateral blood flow
supply, cerebral perfusion
pressure, susceptibility of
tissue to ischemia and
ischemic preconditioning,
location of the vessel
occlusion, and other
specific factors such as
hyperglycemia, body
temperature, and oxygen
delivery capacity.

● In patients with proximal

FIGURE 4-3 cerebral artery occlusions,
The evolution of the ischemic core lesion according to time. no single practical and
CBF = cerebral blood flow; EEG = electroencephalogram; EP = evoked potential.
reliable imaging biomarker
predicts infarct growth into
the surrounding penumbra;
however, the principles of
anterior portion of the circle of Willis. The posterior communicating arteries can clinical-imaging mismatch
equally provide flow in one or the other direction between the anterior and and perfusion-imaging
posterior circulations. Blood flow reversal within the ophthalmic artery is an mismatch have
revolutionized the
important source of secondary collateral support in cases of proximal carotid
evaluation of patients with
occlusion. Distal anastomoses can provide an alternative supply into a major acute ischemic stroke.
arterial territory, mostly between the anterior, middle, and posterior cerebral
arteries but also across the cerebellar arteries in case of vertebrobasilar disease.33,37,38 ● Cerebral collaterals can
The leptomeningeal collateral circulation is a chain of blood vessels supplying the be broadly divided into the
short bypass segments at
brain that follows a diffuse course over the superficial surface of the brain. the circle of Willis and the
Within major pial arterial territories, microscopic anastomoses may help regulate elongated leptomeningeal
alternative vascular supply to local cortical tissue fields.33,39 anastomotic routes able to
The anatomy of the circle of Willis varies considerably. Anatomic studies describe deliver retrograde perfusion
to adjacent vascular
an azygos anterior communicating artery (unpaired anterior communicating artery) territories.
in up to 5% of patients, absence of the anterior communicating artery in 1% of
patients, absence or hypoplasia of the proximal anterior cerebral artery in 10% of
patients, a fetal posterior circulation artery (arising from the internal carotid
arteries) in 20% to 30% of patients, and absence or hypoplasia of either posterior
communicating arteries in 30% of patients.33,40 FIGURE 4-5 summarizes the
collateral circulation of the brain. Such anatomical variations may become even
more important when blood flow is dependent on collaterals.
The collateral circulation also has long been recognized as a factor in
modifying stroke risk in patients with carotid stenosis. Collateral capacity in
patients with internal carotid artery (ICA) occlusive disease as measured by
angiography predicts the presence of CT infarction in patients with transient
ischemic attacks.41,42 In one study, the absence of collateral flow in patients with
ICA occlusions as measured by angiography correlated with low oxygen extraction
fraction on positron emission tomography (PET) scanning and increased
frequency of brain infarcts.43 In a series of patients with unilateral ICA occlusions,
the presence of a posterior communicating artery that measured at least 1 mm
correlated with the absence of border-zone hemispheric infarction.44

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ENDOVASCULAR TREATMENT OF ACUTE ISCHEMIC STROKE

The natural history of proximal intracranial arterial occlusion usually indicates

a poor outcome. However, clinical severity at presentation (eg, baseline National
Institutes of Health Stroke Scale [NIHSS] score) and the presence of collateral
flow seem to be more important than the level of proximal intracranial arterial
occlusion in determining the prognosis. In other words, an occlusion of the
middle cerebral artery (MCA)-M2 segment in a patient presenting with an
NIHSS score of 14 and poor collaterals will, in general, have a worse outcome
than an occlusion of the ICA terminus in a patient presenting with an NIHSS
score of 6 and good collaterals.6,31 Collateral circulation has also been found to be
important in determining the outcome of various acute reperfusion treatments (IV
and intraarterial thrombolysis and mechanical clot retrieval) in patients with acute
brain ischemia.35,45–47 The presence and adequacy of collateral circulation
supplying the brain distal to arterial occlusions is a key prognostic factor. In several
studies, delayed recanalization together with poor collateral vessels correlated with
poor outcome when compared with early recanalization and good collaterals.48,49
Conversely, patients with acute ischemic stroke presenting at later time windows
may still benefit from endovascular therapy if good collaterals are present.45,46
This highlights that, although time to treatment is, on average, a good predictor

CASE 4-2 A 62-year-old woman with a history of atrial fibrillation and dyslipidemia
was admitted to the hospital 5 hours after the sudden onset of a mild
expressive aphasia and a right facial droop.
Her National Institutes of Health Stroke Scale (NIHSS) score at
admission was 3. Her noncontrast head CT had an Alberta Stroke Program
Early CT Score (ASPECTS) of 8 (hypodensities at the caudate and left M4).
CT angiography confirmed a left middle cerebral artery occlusion with
excellent collateral flow (score of 3 in the Souza collateral grading
system). Her core ischemic lesion was 5 mL (cerebral blood flow, less
than 30%) and her hypoperfused area was 6 mL (mismatch ratio, 1.2)
(FIGURE 4-4). The patient was admitted to the stroke unit and managed
conservatively.
Nine hours after hospital admission, the patient became aphasic and
developed a right hemiplegia (NIHSS score, 18). Given the severe clinical
deficits, CT perfusion was not repeated, and she was immediately
treated with mechanical thrombectomy with a modified thrombolysis in
cerebral infarction (TICI) score 2b recanalization (FIGURE 4-2).
A follow-up MRI showed a 30-mL infarct in the left middle cerebral
artery territory. Her 3-month modified Rankin Scale score was 3.

COMMENT This case illustrates the dynamic of the collateral circulation in acute
ischemic stroke. The patient initially had mild neurologic symptoms despite
a large vessel occlusion; therefore, mechanical thrombectomy was not
offered. Even with the best medical treatment, collateral failure happened
9 hours after hospital admission. Neurologic surveillance was of utmost
importance in this case, as it allowed quick identification of worsening and
immediate reperfusion therapy.

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of treatment response, it should not dictate treatment decisions in isolation
because collateral flow prolongs the time of tissue viability.

GRADING COLLATERALS
The role of collateral circulation in selecting patients for endovascular therapies
should not be underestimated. An accurate assessment of the cerebral collateral
circulation is a very important prerequisite for the appropriate management of
patients with acute ischemic stroke. Recently, various imaging criteria have been
developed to grade the collateral status in patients with stroke.31,50 The structure
of the cerebral collateral circulation can be assessed by using transcranial
Doppler (TCD), transcranial color-coded duplex ultrasonography, CT
angiography (CTA), MR angiography (MRA), and digital subtraction
angiography (DSA).33,36
TCD is a noninvasive method that can measure real-time cerebral blood flow
velocities, collateral status, and cerebrovascular reactivity. However, the
accuracy of TCD in diagnosing vessel occlusion and collateral status highly relies
on the experience of the examiner.51,52 MRA is also noninvasive and can be used
to evaluate the structure of cerebral collateral circulation. The accuracy of

FIGURE 4-4
Imaging showing noncontrast head CT (A) with an Alberta Stroke Program Early CT Score
(ASPECTS) of 8, CT angiography (B) confirming a left middle cerebral artery occlusion with
excellent collateral flow (score 3), and an automated perfusion evaluation (C) depicting a
mismatch of 1 mL (core ischemic lesion of 5 mL and hypoperfused area of 6 mL).
CBF = cerebral blood flow; Tmax = time to maximum.

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ENDOVASCULAR TREATMENT OF ACUTE ISCHEMIC STROKE

time-of-flight MRA to evaluate

leptomeningeal collaterals is
limited because of its relatively
low spatial resolution. Moreover,
evaluating unstable patients with
acute ischemic stroke by using
MRI can be cumbersome because
of longer examination times and
the inability to evaluate patients
with a metallic prosthesis or
pacemaker.53–55 Recent advances
in 7-Tesla MRI have made
possible the evaluation of pial
branches in cerebral arterial
disease, opening a new avenue
for assessing leptomeningeal
collaterals with high-resolution
MRA.56 However, this technique
is not feasible in the acute setting.
CTA is another noninvasive
method that has a high accuracy
in assessing the presence of
proximal arterial occlusions.57
Because blood flow via collaterals
may be delayed when compared
with normal antegrade flow,
FIGURE 4-5
Intracranial and extracranial-intracranial arterial traditional single-phase CTA
collateral circulation. Each middle oval indicates may miss the more delayed
the potential connecting vessels between the left phases required to optimally
and right arteries in the intracranial (A) and capture collateral opacification
extracranial-intracranial (B) circulations.
and, as such, may underestimate
collateral flow.58,59 In order
to overcome this limitation,

TABLE 4-1 The American Society of Interventional and Therapeutic Neuroradiology/

Society of Interventional Radiology (ASITN/SIR) Collateral Scalea

Grade Description

0 No collaterals visible to the ischemic site

1 Slow collaterals to the periphery of the ischemic site with persistence of some of the defect

2 Rapid collaterals to the periphery of ischemic site with persistence of some of the defect and to only a portion of the
ischemic territory

3 Collaterals with slow but complete angiographic blood flow of the ischemic bed by the late venous phase

4 Complete and rapid collateral blood flow to the vascular bed in the entire ischemic territory by retrograde perfusion

a
Reprinted with permission from Higashida RT, et al, Stroke.23 © 2003 American Heart Association.

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multiphase CTA (or dynamic CTA) is being increasingly used to assess cerebral KEY POINTS
collateral status.60
● The natural history of
DSA is the gold standard to evaluate the collateral anatomy and dynamics. The proximal intracranial
most largely recognized grading system for collaterals on DSA is the American arterial occlusion is usually
Society of Interventional and Therapeutic Neuroradiology/Society of Interventional that of poor outcomes.
Radiology collateral scale that classifies the cerebral collateral status to grades However, clinical severity
at presentation (eg, baseline
0 to 4 (TABLE 4-1).18 Grades 0 and 1 are considered poor, grade 2 is moderate, and
National Institutes of Health
grades 3 and 4 are good collateral flow.18,61,62 Stroke Scale [NIHSS]
Several CTA-based collateral scales are useful in predicting the volume of score) and the presence
infarct core and the perfusion to diffusion mismatch ratio within the first few of collateral flow seem to
be more important than the
hours after an ischemic stroke. Some examples of collateral grading methods
level of proximal intracranial
based on CTA are shown in TABLE 4-2.11,17,35,60,63,64 arterial occlusion in
determining the prognosis.
NEUROIMAGING FOR SELECTING PATIENTS FOR ACUTE
ENDOVASCULAR THERAPIES ● An accurate assessment
of the cerebral collateral
The baseline Alberta Stroke Program Early CT Score (ASPECTS) is a well-known circulation is a very
predictor of outcome in patients with acute ischemic stroke. Originally important prerequisite for
developed for standardized lesion assessment on noncontrast CT, it is a 10-point the appropriate
scoring system with anatomic regions distributed over the MCA territory.65 management of patients
with acute ischemic stroke.
Many of the pivotal randomized controlled trials that demonstrated a strong
positive effect of mechanical thrombectomy using stent-retriever devices on
clinical outcomes used a noncontrast CT ASPECTS for patient selection.8,9,11 Of
note, the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular
Treatment for Acute Ischemic Stroke in the Netherlands) did not use an
ASPECTS threshold for patient exclusion and showed a consistent additional
effect of intraarterial treatment over all ASPECTS ranges analyzed (0 to 4, 5 to 7,
8 to 10). However, only 30 patients with an ASPECTS of 0 to 4 were evaluated in
the trial.7 A meta-analysis from five early-window thrombectomy trials
suggested that, although a lower baseline ASPECTS was strongly associated with
lower rates of favorable outcomes, a similar benefit was conferred in patients
with an ASPECTS of 9 to 10 and those with an ASPECTS of 6 to 8. However, the
effect of endovascular thrombectomy in patients with a baseline ASPECTS
of 5 or lower could not be established because most trials excluded such
patients (CASE 4-3).12 A recent multicenter, pooled analysis of seven institutional
prospective registries of patients presenting with an ASPECTS of 0 to 5 who were
treated with mechanical thrombectomy showed that successful reperfusion was
beneficial without increasing the risk of symptomatic intracerebral hemorrhage,
suggesting that a formal clinical trial of mechanical thrombectomy versus best
medical treatment in these patients is justified.66
The original ASPECTS has some important limitations: interrater reliability is
low even among experienced physicians; cerebral small vessel disease and
movement of the patient can influence interpretation; most importantly,
the template is based on anatomical structures, and, thus, the individual
regions cover different amounts of brain tissue with varying degrees of tissue
eloquence, and so the score is not a linear scale.67,68 Therefore, infarct location
and laterality, and not just infarct volume, impact clinical outcomes and can
provide additional prognostic value in patients with acute intracranial
vessel occlusion.
CT perfusion (CTP) is a widely accessible method and can be combined with
nonenhanced CT and CTA data, especially in patients with anterior circulation

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ENDOVASCULAR TREATMENT OF ACUTE ISCHEMIC STROKE

stroke. CTP requires a 35- to 50-mL bolus of iodinated contrast delivered by

power injection into an antecubital vein and a dynamic cine image acquired
after a 5- to 7-second delay after the contrast injection. CTP coupled with CTA
provides a broad assessment of collateral circulation and functional and anatomic
aspects.69,70 The physiologic data derived from CTP are displayed in perfusion
maps, including cerebral blood flow, cerebral blood volume, and mean transit
time. Brain regions with critically reduced cerebral blood volume or cerebral
blood flow coincide with the core of the infarction. Areas with prolongation of
the mean transit time or its inferred parameters (time-to-peak and time-to-
maximum) have been shown to appropriately quantify the penumbra in patients
with acute ischemic stroke. It is important to be aware of CTP limitations because
delayed cerebral tissue iodine saturation could occur in the setting of cardiac
arrhythmias, low cardiac output, cervical internal carotid artery stenosis, or a
mixture of these factors, which are not uncommon in patients with acute
ischemic stroke.69,71
The success of the pivotal clinical trials demonstrating the efficacy of
endovascular stroke therapy is mostly attributable to the use of next-generation
mechanical thrombectomy devices, resulting in better recanalization rates, and

TABLE 4-2 CT Angiography Collateral Grading Methods

Tan Collateral Grading System63

◆ Leptomeningeal collateral status graded in source images and maximum intensity
projection reconstructions of single-phase CT angiography (CTA) as:
◇ 0 = No collateral supply to the occluded middle cerebral artery (MCA) territory
◇ 1 = Collateral supply filling ≤50% of the occluded MCA territory
◇ 2 = Collateral supply filling >50% but <100% of the occluded MCA territory
◇ 3 = 100% collateral supply of the occluded MCA territory
Lima Collateral Grading System35
◆ Collateral vessels in the leptomeningeal convexity are graded in CTA source images by
comparing the symptomatic hemisphere with the contralateral unaffected hemisphere as:
◇ 1 = Absent
◇ 2 = Less than the contralateral normal side
◇ 3 = Equal to the contralateral normal side
◇ 4 = Greater than the contralateral normal side
◇ 5 = Exuberant
Miteff Collateral Grading System64
◆ Collateral status is graded in maximum intensity projection reconstructions of single-phase
CTA in axial, coronal, and sagittal planes in patients with MCA occlusion, and graded as:
◇ Good, if major MCA branches are reconstituted distal to the occlusion
◇ Moderate, if some MCA branches are shown in the Sylvian fissure
◇ Poor, if only the distal superficial MCA branches are reconstituted

CONTINUED ON PAGE 321

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to more rigid neuroimaging criteria for the choice of endovascular treatment
candidates.12 The SWIFT PRIME (Solitaire With the Intention For
Thrombectomy as PRIMary Endovascular Treatment) and EXTEND-IA
(Extending the Time for Thrombolysis in Emergency Neurological Deficits–
Intra-Arterial) trials included an assessment of penumbra, largely by CTP.9,10
Interestingly, both trials had the best outcomes in patients undergoing
endovascular treatment within 6 hours from symptom onset with functional
independence at 3 months of follow-up in 60% in the SWIFT PRIME trial and
71% in the EXTEND-IA trial.9,10 CTP is definitely not essential for endovascular
reperfusion candidates in the 0- to 8-hour time window. However, the higher
proportion of good outcomes in the trial that used CTP as a selection tool
suggests that CTP might be helpful in choosing patients with higher chances of
benefiting from the treatment. One should be aware that CTP may cause
significant delays in workflow due to the longer acquisition and processing times,
and it does not invariably provide accurate information, resulting in both
overestimation and underestimation of ischemic core.72,73 Furthermore, the
adoption of strict CTP criteria might lead to overselection by excluding many
patients for whom endovascular therapy could be beneficial.

CONTINUED FROM PAGE 320

Souza Collateral Grading System17

◆ Intracranial CTA maximum intensity projections are used for grading:
◇ 0 = Absent collaterals >50% of an M2 territory
◇ 1 = Diminished collaterals >50% of an M2 territory
◇ 2 = Diminished collaterals <50% of an M2 territory
◇ 3 = Collaterals equal to the contralateral side
◇ 4 = Increased collaterals
ESCAPE (Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke)
Scoring System11,60
◆ Pial arterial filling score within the symptomatic ischemic territory using single-phase and
multiphase CTA; collaterals are scored as below (when compared with the asymptomatic
contralateral hemisphere):
◇ 0 = No vessels visible in any phase within the ischemic vascular territory
◇ 1 = Just a few vessels visible in any phase within the occluded vascular territory
◇ 2 = Delay of two phases in filling in of peripheral vessels and decreased prominence and
extent or a one-phase delay and some ischemic regions with no vessel prominence and
extent of pial arteries
◇ 3 = Delay of two phases in filling in of peripheral vessels or there is a one-phase delay and
significantly reduced number of vessels in the ischemic territory
◇ 4 = Delay of one phase in filling in of peripheral vessels, but prominence and extent is the
same
◇ 5 = Delay and normal or increased prominence of pial vessels/normal extent within the
ischemic territory in the symptomatic hemisphere

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ENDOVASCULAR TREATMENT OF ACUTE ISCHEMIC STROKE

The use of MRI as a neuroimaging method for hyperacute stroke has been
incorporated by some stroke centers. Current stroke MRI protocols can be
performed in only 5 to 20 minutes. The diffusion-weighted image lesion volume
is directly associated with the degree of collateral flow in acute ischemic stroke.
Large lesion volumes and cortical lesion patterns (regardless of the lesion
volume) on diffusion-weighted imaging are frequently found in patients with

CASE 4-3 A 72-year-old man was

admitted to the hospital
4 hours after a sudden onset
of left hemiplegia and
hemineglect, dysarthria,
and forced eye deviation
to the right.
His National Institutes
of Health Stroke Scale score
at hospital admission was
22. His noncontrast head CT
had an Alberta Stroke
Program Early CT Score
(ASPECTS) of 4. CT
angiography confirmed a
right middle cerebral artery
(MCA) occlusion with very
poor collateral flow (score
of 0 in the Souza collateral FIGURE 4-6
The panel from the patient in CASE 4-3 shows
grading system) (FIGURE 4-6).
noncontrast head CT (A) with an Alberta Stroke
His core ischemic lesion was Program Early CT Score (ASPECTS) of 4, CT
62 mL (cerebral blood flow, angiography (B) confirming a right middle cerebral
less than 30%), and his artery occlusion with very poor collateral flow
(score 0), and an automated perfusion evaluation
hypoperfused area was
(C) depicting a mismatch ratio of 1.8 (core ischemic
114 mL (mismatch ratio, 1.8). lesion of 62 mL and hypoperfused area of 114 mL).
He was treated with IV CBF = cerebral blood flow; Tmax = time to maximum.
recombinant tissue
plasminogen activator (rtPA)
with no improvement. Mechanical thrombectomy was not offered based
on the poor collateral flow profile. The patient developed a malignant
MCA syndrome. His family decided against hemicraniectomy and
comfort measures only were instituted. The patient died 7 days after
hospital admission.

COMMENT This patient had a malignant collateral profile, and, therefore, mechanical
thrombectomy was not offered. It is still a matter of controversy of how to
treat patients with large cores and large mismatch ratios. Future studies
need to address the role of intravenous and endovascular recanalization in
this patient population.

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poor collaterals.54,74,75 Even though diffusion-weighted imaging is a more reliable KEY POINTS
marker for ischemic core than CTP, diffusion abnormalities can still be reversed
● The success of the pivotal
and fully salvaged with rapid reperfusion in some patients.76 Therefore, it is clinical trials demonstrating
important to continue to study patients undergoing reperfusion to establish the efficacy of endovascular
models that can better predict what will happen in the best-case scenario of early stroke therapy is mostly
and sustained recanalization. attributable to the use of
next-generation mechanical
thrombectomy devices,
AUTOMATED PERFUSION READING resulting in better
Negative trials using the “mismatch” concept have suggested that visual recanalization rates, and to
assessment can be unreliable and that thresholds are required to better more rigid neuroimaging
criteria for the choice of
distinguish benign oligemia from critical hypoperfusion and ischemic core in
endovascular treatment
patients with acute ischemic stroke.77,78 Several studies have shown that candidates.
automated processing of CTP and MRI can provide a quantitative mismatch
classification even among inexperienced neuroimaging centers (CASE 4-1, ● CT perfusion might be
CASE 4-2, and CASE 4-3). Furthermore, in clinical practice, automated CTP helpful in choosing patients
with higher chances of
processing seems to improve diagnostic confidence by eliminating the need for benefiting from the
postprocessing and thus increasing reproducibility of interpretation. Therefore, treatment. However,
less experienced centers can take better advantages of its use.79,80 clinicians should be aware
The higher rates of good outcomes in the trials that used automated perfusion that CT perfusion may cause
significant delays in
reading of CTP in the classical time window of 6 hours from symptom onset workflow due to the longer
(SWIFT PRIME and EXTEND-IA) when compared with those that mainly used acquisition and processing
noncontrast CT ASPECTS (REVASCAT [Endovascular Revascularization With times, and it does not
Solitaire Device Versus Best Medical Therapy in Anterior Circulation Stroke invariably provide accurate
information, resulting in
Within 8 Hours], ESCAPE [Endovascular Treatment for Small Core and
both overestimation and
Proximal Occlusion Ischemic Stroke], and MR CLEAN) suggest that refining underestimation of
selection with CTP imaging may optimize clinical results in the treated ischemic core.
patients.7–11 However, it is important to understand a critical limitation of this
finding because the outcomes were reported only for the treated patients ● Several studies have
shown that automated
meeting the inclusion criteria for the respective trials. Therefore, it becomes processing of CT perfusion
critical to account for the denominator effect. As more patients are excluded and MRI can provide a
from treatment due to more strict selection criteria, the outcomes for the overall quantitative mismatch
population that is initially considered for treatment might actually be worse classification even among
inexperienced neuroimaging
than if simpler, faster, and more inclusive criteria are used. A simple illustration centers.
of this phenomenon is that the control population of EXTEND-IA (100% CTP
selection) had better outcomes than the endovascular arm of MR CLEAN (very
inclusive treatment criteria).7,10
The time delays that can be potentially caused by CTP imaging, its costs and
risks, and the chances of super-selecting patients for endovascular treatment
should be further evaluated.72

ENDOVASCULAR THERAPY WITHIN 6 HOURS FROM SYMPTOM ONSET

In 2015, the paradigm of acute ischemic stroke treatment for patients with large
vessel occlusion shifted definitely to endovascular therapy. Six randomized
controlled trials undoubtedly confirmed the benefits of using endovascular
thrombectomy on the clinical outcome of patients with stroke compared with
those receiving only standard medical care.7–9,11,81 The trials MR CLEAN, SWIFT
PRIME, and EXTEND-IA proved the benefit of mechanical thrombectomy in
anterior circulation acute ischemic stroke within the first 6 hours of symptom
onset.7,9,10 The THRACE trial (Trial and Cost Effectiveness Evaluation of
Intra-arterial Thrombectomy in Acute Ischemic Stroke) added further evidence

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ENDOVASCULAR TREATMENT OF ACUTE ISCHEMIC STROKE

for thrombectomy up to 5 hours from symptom onset.81 Finally, the ESCAPE

and REVASCAT trials proved the benefit of mechanical thrombectomy for
patients with anterior circulation acute ischemic stroke up to 8 hours from
symptom onset.8,11
In a meta-analysis of individual patient data (including MR CLEAN,
REVASCAT, ESCAPE, SWIFT PRIME and EXTEND-IA [HERMES]), the
number needed to treat with endovascular thrombectomy to reduce disability by
at least one level on the modified Rankin Scale score for one patient was 2.6.12
Furthermore, HERMES corroborated the benefit of endovascular thrombectomy
across a range of subgroups, including in patients not receiving IV rtPA, elderly
patients, and patients arriving later than 5 hours from stroke symptom onset.12
Based on the selection criteria and results of the six trials discussed herein, the
American Heart Association recommends that patients should receive
mechanical thrombectomy with a stent retriever if they meet all the criteria
described in TABLE 4-3.82
The use of mechanical thrombectomy in patients with MCA M2 occlusions
within 6 hours from symptom onset may be reasonable for carefully selected
patients, as is its use in patients who have a prestroke modified Rankin Scale
score greater than 1, ASPECTS less than 6, or NIHSS score less than 6.82 The
benefit of mechanical thrombectomy in patients presenting within 6 hours from
symptom onset and occlusion of the anterior cerebral arteries, vertebral arteries,
basilar artery, or posterior cerebral arteries remains uncertain.82
It is important to highlight that, in all trials previously described, patients
received IV thrombolysis as a bridge to mechanical thrombectomy when eligible
and that the chances of better outcomes at 90 days within the mechanical
thrombectomy group declined with a longer time from symptom onset to arterial
puncture. Therefore, observation after IV thrombolysis to evaluate clinical
improvement before mechanical thrombectomy should not be performed.12,82
The goal of mechanical thrombectomy should be to achieve reperfusion, not
only recanalization. There are several reperfusion scores; however, the modified
thrombolysis in cerebral infarction (TICI) score is currently the tool with a better
correlation with clinical outcomes and should, therefore, be used (FIGURE 4-2).
The final objective of the mechanical thrombectomy procedure should be a
reperfusion to a modified TICI score of either 2b or 3.23–25,82
In all pivotal clinical trials of mechanical thrombectomy in acute ischemic
stroke, stent retrievers were used. In the procedure, a catheter is advanced into
an artery, and by using x-ray guided imaging, a stent retriever is inserted into the

TABLE 4-3 Characteristics of Candidates for Endovascular Therapy Within 6 Hours of

Last Known Normal With Large Vessel Occlusion

◆ No important previous disability (prestroke modified Rankin Scale score of 0 to 1)

◆ Occlusion of the internal carotid artery or middle cerebral artery segment 1
◆ Age ≥18 years
◆ National Institutes of Health Stroke Scale (NIHSS) score ≥6
◆ Alberta Stroke Program Early CT Score (ASPECTS) ≥6
◆ Treatment can be initiated within 6 hours of symptom onset

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catheter.7–11,81 The stent reaches past the clot, expands to stretch the walls of the KEY POINT
artery, and is retrieved, removing the clot. Direct aspiration thrombectomy as
● Recently, two clinical
first-pass mechanical thrombectomy was proven to be noninferior to stent trials completely disrupted
retrievers for patients treated within 6 hours from symptom onset.83,84 the time window concept in
Therefore, both second-generation stent retrievers and aspiration devices can be acute ischemic stroke,
used for mechanical thrombectomy in acute ischemic stroke.82,85 Stent retrievers showing excellent clinical
outcomes in patients
can also be used in combination with aspiration techniques. Local expertise and
treated up to 24 hours
availability will influence the decision to use either technique (FIGURE 4-7 from symptom onset;
and FIGURE 4-8). effectiveness of late-
window thrombectomy was
maintained across all
EXPANDING THE TIME WINDOW
subgroups, including those
Recently, two clinical trials completely disrupted the time window concept in defined by time, age, mode
acute ischemic stroke, showing excellent clinical outcomes in patients treated up of presentation, and the
to 24 hours from symptom onset.13,14 The DAWN (DWI or CTP Assessment Alberta Stroke Program
With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Early CT Score (ASPECTS).

Undergoing Neurointervention) trial included patients at a median of 12.5 hours

from onset and showed the largest treatment effect size in terms of functional
outcome ever described in any acute stroke treatment trial (35.5% increase in
functional independence).13 In DEFUSE 3 (Endovascular Therapy Following
Imaging Evaluation for Ischemic Stroke 3), patients treated with mechanical
thrombectomy at a median of 11 hours after onset had a 28% increase in
functional independence and an additional 20% absolute reduction in death or
severe disability.14 These astonishing results led to the question of why the
treatment effect was larger in the late-window trials, which has been called
the late-window paradox. This is, in part, because large vessel occlusions can
respond to IV rtPA, and because both DAWN and DEFUSE 3 randomly assigned
patients only after 6 hours from the time last seen well, the vast majority of
the controls did not have the benefit of IV rtPA. In fact, the controls of DAWN
and DEFUSE 3 had the worst outcomes of any mechanical thrombectomy trial

FIGURE 4-7
Example of the use of a stent retriever in a patient with acute ischemic stroke and large vessel
occlusion. A, B, An occlusion of the right middle cerebral artery. C, D, Complete
recanalization (modified thrombolysis in cerebral infarction [TICI] score of 3). E, The stent
retriever and the thrombi.

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ENDOVASCULAR TREATMENT OF ACUTE ISCHEMIC STROKE

FIGURE 4-8
Example of the use of an aspiration device in a patient with acute ischemic stroke and large
vessel occlusion. A, B, An occlusion of the right middle cerebral artery (arrows), C, D, The
deployment of an aspiration device (arrows). E, F, Complete recanalization (modified
thrombolysis in cerebral infarction [TICI] score of 3).

despite the fact that they had small infarcts on presentation. Another factor is
that the growth of early ischemic lesions varies substantially among patients.
Some patients with very poor collateral circulation develop large ischemic
lesions in the first hours after symptom onset whereas other patients present
with very small lesions even after 12 hours of stroke symptoms. In nonreperfused
patients, lesion volumes usually reach their peak in 3 days. In the DEFUSE 2
study (Diffusion and Perfusion Imaging Evaluation for Understanding Stroke
Evolution Study 2), about 30% of the patients presented with a medium
growth range (3 mL/h to 10 mL/h), and only 20% had a malignant profile, and
growth rates ranged from about 15 mL/h to as high as 100 mL/h. Both studies
(DAWN and DEFUSE 3) used automated software to determine the ischemic
core. Because of the requirement for small core volumes, most of the patients
included in the DAWN and DEFUSE 3 studies had slow progressions.
Considering that the median time from symptoms to enrollment was 12.5 hours
in DAWN and 11 hours in DEFUSE 3 and core volumes were ≤10 mL, the early
growth rates of the infarcts in both studies were ≤1 mL/h before enrollment.
Therefore, both trials enrolled patients who were very slow progressors.86
Interestingly, effectiveness of late-window thrombectomy was maintained
across all subgroups, including those defined by time, age, mode of presentation,
and ASPECTS. Patients with witnessed onset of symptoms at 6 to 24 hours
derived comparable benefit to patients with wake-up stroke and unwitnessed
mode of presentation.13,14,87

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CARE DURING AND AFTER MECHANICAL THROMBECTOMY KEY POINTS
There is uncertainty if either general anesthesia or conscious sedation should be
● Outcomes after
used in patients undergoing mechanical thrombectomy.82 Three single-center mechanical thrombectomy
randomized clinical trials compared general anesthesia with conscious sedation seem to depend on the
during acute ischemic stroke endovascular procedures.88–90 In none of the trials was interaction of several
general anesthesia superior to conscious sedation for the primary end point, but variables including infarct
volume, regional eloquence,
patients treated with general anesthesia had better outcomes in several clinical
age, and baseline functional
secondary end points. However, many retrospective studies suggest that general status.
anesthesia in patients undergoing mechanical thrombectomy is associated with
worse functional outcomes, including a post hoc analysis of the MR CLEAN trial.91–93 ● The safety profile in the
Blood pressure is probably the most important isolated parameter to be late time window seems to
be similar to mechanical
monitored during and after an endovascular procedure for acute ischemic stroke. thrombectomy performed in
From the periprocedural period to days later, the cerebral autoregulation is up to 6 hours from symptom
impaired, and the patient is susceptible to complications caused by transient onset.
changes in blood pressure levels.94 Many patients treated with mechanical
thrombectomy will have been treated with IV thrombolysis and, therefore,
should have their systolic/diastolic blood pressure maintained at ≤180/105 mm
Hg. No randomized clinical trials have evaluated ideal blood pressure levels in
patients undergoing mechanical thrombectomy. In the trials evaluating patients
within 6 hours from symptom onset, as many patients were treated with IV rtPA,
blood pressure was maintained at ≤180/105 mm Hg for 24 hours after the
procedure. Normal blood pressure levels were recommended once recanalization
was achieved in ESCAPE, as well as in the DAWN trial, which recommend
systolic blood pressure <140 mm Hg for the first 24 hours in patients who achieve
complete recanalization.11,13 The ideal blood pressure levels during and after
mechanical thrombectomy deserve further investigation.

CONCLUSION
For patients with acute ischemic stroke and a large vessel occlusion in the
proximal anterior circulation who can be treated within 6 hours of stroke
symptom onset, mechanical thrombectomy with a second-generation stent
retriever or a catheter aspiration device should be indicated whether or not the
patient received treatment with IV rtPA in patients with limited signs of early
ischemic changes on neuroimaging.82 Two clinical trials completely disrupted the
time window concept in acute ischemic stroke, showing excellent clinical
outcomes in patients treated up to 24 hours from symptom onset.13,14
Outcomes after mechanical thrombectomy seem to depend on the interaction
of several variables including infarct volume, regional eloquence, age, and
baseline functional status. In patients with a mismatch (either clinical-imaging
or perfusion-core mismatch), endovascular treatment initiated more than
6 hours and up to 24 hours from time last seen well is a highly effective therapy
and not less effective than treatment within 0 to 6 hours.86 The safety profile in
the late time window seems to be similar to mechanical thrombectomy
performed in up to 6 hours from symptom onset. Effectiveness is maintained
across all prespecified subgroups (across age, mode of presentation, and
ASPECTS).13,14
DAWN and DEFUSE3 had demonstrated a strong benefit of thrombectomy in
properly selected stroke patients treated within the 6- to 24-hour window.
However, as suggested by the large treatment effect size observed in both trials,

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ENDOVASCULAR TREATMENT OF ACUTE ISCHEMIC STROKE
the clinical-imaging mismatch and the perfusion-core mismatch criteria were
very likely too stringent. Future studies should focus on better establishing the
minimum boundaries of benefit in this patient population.
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