Review Article
Address correspondence to
Dr Alejandro Rabinstein, Mayo
Clinic, Department of
Neurology, W8B, 200 First St
SW, Rochester, MN 55905,
rabinstein.alejandro@mayo.edu.
Relationship Disclosure:
Dr Rabinstein serves as an
associate editor for
Neurocritical Care; on the
editorial boards of Continuum:
Lifelong Learning in Neurology,
the Journal of Stroke and
Cerebrovascular Diseases,
Neurology, and Stroke; and on
the scientific advisory board of
Portola Pharmaceuticals, Inc.
Dr Rabinstein receives research/
grant support from DJO Global,
Inc, and royalties from Elsevier,
Oxford University Press, and
UpToDate, Inc.
Unlabeled Use of
Products/Investigational
Use Disclosure:
Dr Rabinstein reports
no disclosure.
* 2017 American Academy
of Neurology.
62
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Treatment of Acute
Ischemic Stroke
Alejandro A. Rabinstein, MD, FAAN
ABSTRACT
Purpose of Review: This article provides an update on the state of the art of the
emergency treatment of acute ischemic stroke with particular emphasis on the
alternatives for reperfusion therapy.
Recent Findings: The results of several randomized controlled trials consistently
and conclusively demonstrating that previously functional patients with disabling
strokes from a proximal intracranial artery occlusion benefit from prompt recanaliza-
tion with mechanical thrombectomy using a retrievable stent have changed the
landscape of acute stroke therapy. Mechanical thrombectomy within 6 hours of
symptom onset should now be considered the preferred treatment for these patients
along with IV thrombolysis with recombinant tissue plasminogen activator (rtPA) within
the first 4.5 hours for all patients who do not have contraindications for systemic
thrombolysis. Patients who are ineligible for IV rtPA can also benefit from mechanical
thrombectomy. Collateral status and time to reperfusion are the main determinants
of outcome.
Summary: Timely successful reperfusion is the most effective treatment for patients
with acute ischemic stroke. Systems of care should be optimized to maximize the
number of patients with acute ischemic stroke able to receive reperfusion therapy.
Continuum (Minneap Minn) 2017;23(1):62–81.
INTRODUCTION This
Over the past 2 decades, the thera- article
peutic approach to acute ischemic primarily
stroke has been deeply transformed. focuses on
Long gone is the nihilism of former reperfusion
times, now replaced by the excite- strategies
ment of proven treatment options that because
can reverse ischemia and bring back these
function to patients who were otherwise
destined to death or severe disabil-
ity. The wide adoption of IV thrombol-
ysis that began 20 years ago has recently
been followed with clear evidence
that the addition of endovascular treat-
ment with mechanical thrombectomy
can further improve outcomes in pa-
tients with severe neurologic defi-
cits from a proximal intracranial vessel
occlusion.
62
ContinuumJournal.com February 2017
 Review Article
treatments are the most effective in- terventions for acute
ischemic stroke. However, the treatment of acute stroke also
includes adequate hemo- dynamic management, monitoring and
management of ischemic brain edema, and early recognition of
and therapy for systemic complications (such as infections, cardiac
arrhyth- mias, heart failure, and venous throm- boembolism) in a
stroke unit staffed by specially trained personnel. The
management of acute ischemic stroke starts with the prompt
recognition of the diagnosis in the field, and atten- tion is
currently aimed at optimizing the time to reperfusion in the
emer- gency department and the angio- graphic suite. However,
what happens in the stroke unit or intensive care unit after
hospitalization is also very

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 Review Article

exceed what would be

important to maximize the chances of of presentation and why neurologic
expected for the
good recovery. Comprehensive guide- function can improve after
lines offer useful advice in these addi- established infarct core at
reperfu- sion. This collateral flow,
the time
tional areas.1 however, is often tenuous and can
sustain viability only for a limited
PRINCIPLES OF ACUTE period of time. Thus, without
STROKE CARE recanalization, the ischemic
The three main principles of acute penumbra is destined to progress
stroke care are: (1) achieve timely to infarction. Collateral flow can be
recanalization of the occluded artery pro- tected by avoiding blood pressure
and reperfusion of the ischemic tis- drops and supported by the
sue, (2) optimize collateral flow, and administration of IV fluids. The
(3) avoid secondary brain injury. value of keeping the head of the bed
Recanalization and reperfusion are flat for patients with acute ischemic
the mainstay of acute stroke treatment stroke is being investi- gated in the
and can reduce infarct size and re- ongoing Head Position in Stroke
verse neurologic deficits. Recanaliza- Trial (HeadPoST) and should be
tion is defined by the degree of weighed against the risk of
reopening of the occluded artery. aspiration.3
Reperfusion is measured by the de- Hemodynamic augmentation with
gree of flow reaching the previously va- sopressors may be beneficial in
hypoperfused brain region. Opening well- selected cases (such as
the occluded artery works because, in patients with cervical internal carotid
most cases, when the occlusion oc- artery occlusion without tandem
curs, an area of brain tissue becomes intracranial occlusion), but the safety
hypoperfused but is initially not in- and efficacy of this strat- egy is
farcted. This tissue represents the otherwise unknown. Invasive in-
ischemic penumbra that can be sal- terventions to improve collateral
vaged if adequate blood flow is flow remain investigational.
promptly reestablished. Advanced Despite promising results in
brain imaging with CT perfusion or basic
magnetic resonance (MR) diffusion/ and translational experiments,
perfusion can visualize this tissue at numer- ous neuroprotective agents
risk (penumbra imaging).2 Chemical have failed to improve outcomes in
thrombolysis with recombinant tissue clinical trials. Yet, avoidance of
plasminogen activator (rtPA), also secondary insults is a form of
known as alteplase, and mechanical neuroprotection. Hypoglyce- mia
embolectomy with a retrievable stent can exacerbate energy failure and
are the two evidence-based strategies should be strictly averted.
to achieve reperfusion. Hyperglyce- mia might also be
Collateral flow is responsible for deleterious; so far, we know that it
keeping the ischemic penumbra via- correlates with worse outcomes
ble. It provides enough flow to pre- after an ischemic stroke but do not
vent critical ischemia and infarction have proof that its correction
but not sufficient flow to maintain improves outcomes.4 The Stroke
normal cellular function. This explains Hy- perglycemia Insulin Network
why the acute neurologic deficits Effort (SHINE) trial is a randomized
controlled trial comparing tight

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 Review Article
glycemic control with IV insulin to maintain a KEY POINTS
glucose level between 80 mg/dL and 130 mg/dL versus h Prompt reperfusion
is the most effective
standard glycemic control using subcutaneous insulin
treatment for patients
dosed according to a sliding scale to keep the
with acute
glucose level lower than 180 mg/dL in patients with ischemic stroke.
acute ischemic stroke within
12 hours of symptom onset.5 It is h The three principles of acute
stroke therapy are to achieve
recanalization of the occluded
vessel (and reperfusion of the
ischemic tissue), to optimize
collateral flow, and to avoid
secondary brain injury.
h The ischemic penumbra is
the region of hypoperfused
brain that can still be viable
with prompt recanalization
of the occluded artery.
h Collateral flow is
responsible for the
temporary
preservation of the
ischemic penumbra.
h No neuroprotective agent
has been proven to be
beneficial for acute ischemic
stroke in clinical trials.

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 Acute Ischemic Stroke
KEY POINTS
h IV thrombolysis with
rtPA and endovascular
thrombectomy with
a retrievable stent are
both solidly established
treatments for
appropriate candidates
with acute
ischemic stroke.
h Time to reperfusion is a
major determinant of
outcome in acute
ischemic stroke.
h Randomized
placebo-controlled trials
have demonstrated that
IV thrombolysis with
rtPA is beneficial for
patients with acute
ischemic stroke up to
4.5 hours from
symptom onset.
h Some previously cited
contraindications for IV
thrombolysis have been
revisited, thus expanding
the pool of patients
who can be considered
good candidates for
this treatment.
Continuum (Minneap Minn) 2017;23(1):62–81
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Administration (FDA) has only ap- proved rtPA for
hoped that this trial will answer the
use within 3 hours of
question whether tight glycemic control
is safe and beneficial after an acute is-
chemic stroke. Fever is associated with
worse clinical results; thus, treating fever
may be beneficial.6 The value of hypo-
thermia continues to be investigated.
Preventing infections (which notably
includes dysphagia assessment before
any oral intake) and early recurrent
strokes are additional priorities in the
care of the patient with acute stroke.
ACUTE REPERFUSION
TREATMENTS
There is incontrovertible evidence
that IV thrombolysis with rtPA and
endovascular thrombectomy with a
retrievable stent improve neurologic
outcomes in patients with acute ische-
mic stroke. Both treatments should
be administered as quickly as possi-
ble after stroke onset, can be com-
bined, and are safe in appropriately
selected candidates.
IV thrombolysis and mechanical
thrombectomy can produce reperfu-
sion injury after recanalization. Re-
perfusion injury can manifest with
hemorrhage and edema. It is more
severe when the area of established
infarction is larger. Good patient se-
lection (ie, absence of a large ischemic
core) and prompt treatment are cru-
cial to avoid this complication.
Intravenous Thrombolysis
IV thrombolysis with rtPA is proven to
be effective in improving functional
outcomes after an ischemic stroke up
to 4.5 hours after symptom onset.1,7Y9
Randomized controlled trials8,9 fol-
lowed by large observational studies
confirming the rates of recovery noted
in these trials10 and meta-analyses7
support this therapeutic indication
(Figure 3-111). The US Food and Drug
ContinuumJournal.com 66
 Acute Ischemic Stroke
oke onset. Recently, the indications and contra-
stroke
The initial evaluation indications for IV rtPA have been re-
onset, but
of a patient with a visited in a scientific statement of the
regulatory
possible acute stroke in American Heart Association (AHA) 12
agencies in
the emergency and modified by the FDA in the pack-
most other
countries
department should focus age insert for the drug (Table 3-113).
on establishing whether As a result, more patients can be con-
(including
the patient is eligible for sidered for IV thrombolysis in clinical
those in the
reperfusion therapy. Nec- practice. IV thrombolysis should not be
European
essary information withheld because of advanced age, and
Union)
includes the time the mild but disabling deficits justify treat-
have
patient was last known to ment. Individualized clinical judgment
approved
be well, medical is necessary when deciding whether to
its
conditions or recent recommend thrombolysis to patients
administrat
surgery that could with weaker indications (such as non-
ion within
contraindicate disabling deficits) or relative contrain-
4
thrombolysis, neurologic dications. The safety and efficacy of
.
examination to calculate IV thrombolysis in pediatric patients
5
h the National Institutes of (younger than 18 years of age) is not
o Health Stroke Scale well established.
u (NIHSS) score, a capillary IV rtPA infused within 3 hours of
r glucose level, blood symptom onset increases the chances
s pressure, and brain of functional independence at 3 months
o imaging (CT scan with or by one-third.7,8 The benefit is time de-
f without a CT angio- gram pendent and much stronger when the
s depending on whether drug is administered within the first
t endovas- cular therapy is 90 minutes after symptom onset (esti-
r being considered). mated number necessary to treat to help

64 ContinuumJournal.com February 2017

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 Acute Ischemic Stroke

KEY POINT
h Benefit from IV
thrombolysis is much
greater in the first
90 minutes from
symptom onset.

Results of meta-analysis of individual data from major randomized trials of IV

FIGURE 3-1
stroke showing
recombinant that plasminogen
tissue thrombolysisactivator
increases(rtPA)
the chances of achieving
(alteplase) a modified
for acute ischemic
Rankin Scale score of 0 to 1 (no symptoms or mild symptoms with no disability) at 90 days.
Notice that the benefit is time dependent and no longer significant when the drug is
administered more than 4.5 hours after symptom onset. Treatment is beneficial in patients older
than 80 years, and the benefit is fairly consistent across all degrees of initial stroke severity.
CI = confidence interval; NIHSS = National Institutes of Health Stroke Scale.
Reprinted with permission from Emberson J, et al, Lancet Neurol.11 B 2014 Emberson et al. thelancet.com/journals/
lancet/article/PIIS0140-6736(14)60584-5/fulltext.

one more patient achieve functional 3310 predominantly Asian patients to

independence is 3.6 within the first
90 minutes and 4.3 between 91 and
180 minutes) 14 (Case 3-1). Older
patients and those with a very severe
stroke at presentation have worse
prognosis15 but can still benefit from
IV rtPA. The benefit is less robust
for patients treated between 3 and
4.5 hours, but rtPA is still beneficial in
this extended window (number neces-
sary to treat 5.9).9,14
The standard dose of IV rtPA for
acute ischemic stroke is 0.9 mg/kg,
with 10% administered as a bolus and
the remainder infused over 1 hour.
The total dose should not exceed
90 mg. The phase 3 Enhanced Control
of Hypertension and Thrombolysis
Stroke Study (ENCHANTED) enrolled

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 Acute Ischemic Stroke
receive can receive the bolus of rtPA and then
either 0.9 be transferred to a primary stroke
mg/kg or center or compre- hensive stroke center
0.6 mg/kg while the rest of the dose of the drug
of IV rtPA is being infused (the drip-and-ship
within 4.5 strategy).
hours of Hemorrhage is the most dangerous
stroke complication after thrombolysis. The
onset.16
The
reduced
dose was
inferior to
the
standard
dose for
the end
point of
death or
any degree
of
disability at
90 days,
although it
was
associated
with a
lower risk
of
symptomat
ic
intracere-
bral
hemorrhag
e (which
was low in
both
treatment
groups).
No other thrombolytic agent has
been
approved
for use in
ischemic
stroke. In
emergency
departmen
ts of
medical
centers
with more
limited
capabilities
, patients
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 Acute Ischemic Stroke

TABLE 3-1 Indications and Contraindications for IV Recombinant Tissue Plasminogen Activator
American Heart Association American Heart Association US Food and Drug Administration
Guideline 20131 Scientific Statement 201512 (FDA) Package Insert 2015 13
Indications

Diagnosis of ischemic stroke with Same Same

measurable neurologic deficit

Symptom onseta within 4.5 hours Same Within 3 hours

Age Q18 years Same Warning for age 977 years with risk
factors for intracranial hemorrhage
Contraindications
Severe head trauma within Same Contraindicated
3 months

Ischemic stroke within 3 months Risk increased, but degree is unclear Removedb
Arterial puncture at Risk uncertain Not listed
noncompressible site within
7 days
Previous intracranial Same Warning for recent intracranial
hemorrhage hemorrhage (contraindicated if
active intracranial hemorrhage)
Suspected subarachnoid Same Contraindicated
hemorrhage

Intracranial neoplasm, Probably recommended if extraaxial Contraindicated

arteriovenous malformation
(AVM), or aneurysm
neoplasm is present; not
recommended if intraaxial neoplasm
is present; risk unclear for AVM;
probably recommended if unruptured
unsecured aneurysm G10 mm is
present, but risk unclear if greater size

Recent intracranial or Same Contraindicated

intraspinal surgery
(within 3 months)

Active internal bleeding Same Contraindicated

Systolic blood pressure (BP) Same, but treatment recommended Contraindicated for severe uncontrolled
9185 mm Hg or diastolic BP if BP can be lowered safely hypertension (BP values removedb);
9110 mm Hg warning for BP 9175/110 mm Hg

Bleeding diathesis Consider case by case in patients Contraindicated for bleeding

with history of bleeding diathesis; diathesis (laboratory
International normalized
ratio (INR) 91.7 3 not recommended if INR 91.7, low-molecular-weight
Platelets G100,000/mm
heparinoid within 24 hours, direct thrombin inhibitor or
Heparin within 48 hours with Current use of direct factor Xa inhibitor within 48 hours (unless coagulation
abnormal activated partial thrombin inhibitor or testsc are normal)
thromboplastin time factor Xa inhibitor

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 Acute Ischemic Stroke
values removedb)
c
with abnormal coagulation tests Continued on page 67

66 ContinuumJournal.com February 2017

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 Acute Ischemic Stroke

American Heart Association American Heart Association US Food and Drug Administration
Guideline 20131 Scientific Statement 201512 (FDA) Package Insert 201513
Contraindications (continued)

Blood glucose G50 mg/dL Consider recombinant tissue Removedb

plasminogen activator (rtPA) if deficits
still present after glucose normalization

CT showing hypodensity 91/3 Same Removedb

of the cerebral hemisphere
Relative contraindications

Minor stroke (typically rtPA should be administered to patients Removedb

National Institutes of Health with mild but disabling symptoms
Stroke Scale [NIHSS] score G5) within 3 hours of onset; possible risk and
benefit should be weighed in patients
with nondisabling symptoms

Rapidly improving symptoms rtPA should be administered if Not listed

symptoms are still disabling
Pregnancy rtPA may be considered in moderate Warning (Category C)
to severe stroke when anticipated
benefit outweighs the anticipated
risk of uterine bleeding

Seizure at onset with rtPA administration is reasonable Removedb

postictal residual deficits if residual deficits are thought
to be caused by a stroke

Major extracranial trauma rtPA can be considered Warning for recent trauma
within 14 days

Major surgery within 14 days rtPA can be considered in carefully Warning for recent surgery
selected cases

Gastrointestinal or genitourinary Consider rtPA if no structural Warning

surgery within 21 days bleeding lesions

Acute myocardial infarction
within 3 months
Additional contraindications for
3- to 4.5-hour window
Administer rtPA (stroke dose) if concurrent Not listed
stroke and acute myocardial infarction
(MI); it is also reasonable to give rtPA
after recent MI unless it was a STEMI
involving the left anterior myocardium

Age 980 years rtPA recommended

Warfarin use (regardless rtPA probably recommended if INR G1.7 FDA has not approved rtPA for
of INR) use after 3 hours

NIHSS 925 Risk and benefit uncertain

Previous stroke or diabetes mellitus rtPA probably recommended

CT = computed tomography; STEMI = ST-segment elevation myocardial infarction.

b
a
Continuum
Last (Minneap Minn) 2017;23(1):62–81
known well. ContinuumJournal.com 67
The term removed is used to denote a change compared with the previous version of the package insert (2009).
c
Activated partial thromboplastin time, INR, platelet count, ecarin clotting time, thrombin time, factor Xa activity assays.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Acute Ischemic Stroke

KEY POINT
h Most cases of
symptomatic intracerebral
hemorrhage are caused
by reperfusion injury
causing hemorrhagic
transformation of an
already severe stroke.
Case 3-1
A 54-year-old woman presented with the sudden onset of left-sided
weakness and dysarthria. Her husband promptly called 911, and the
patient arrived by ambulance to the emergency department 15 minutes
after symptom onset. Her National Institutes of Health Stroke Scale (NIHSS)
score was 6. Noncontrast CT scan showed no hemorrhage, acute ischemic
changes, or hyperdense vessel sign. She had no contraindications for
thrombolysis. IV rtPA was started 32 minutes after symptom onset. Within
the following 2 hours, the patient improved remarkably, and the following
day she had no residual symptoms.
Comment. The benefit from IV thrombolysis for patients with acute
ischemic stroke is highly dependent on time to administration.
Administration of the bolus within 60 to 90 minutes affords maximal
chances of improvement. In order to treat patients within this short time
window, it is essential to optimize the efficiency of early evaluation, CT
scanning, and drug delivery. In the United States, stroke centers are
expected to be able to consistently administer IV rtPA within 60 minutes of
patient arrival to the emergency department.

reported rates of symptomatic intrace- consists of control of hypertension (sys-

rebral hemorrhage (sICH) have varied
(between 1.9% and 6.4%), depending
on its definition and the design of the
study.17 However, most cases of sICH
are caused by reperfusion injury and
worsen strokes that were already
severe and destined to be disabling.
Hemorrhagic transformation of a large
infarction can increase the risk of
death, but sICH rarely negates what
would have otherwise been a good
recovery. In fact, the number needed
to harm for IV rtPA has been estimated
to be 126 for the combined end point
of disability or death.18 The risk of
sICH is increased with old age, diabe-
tes mellitus, severe hyperglycemia,
uncontrolled hypertension, and larger
hypodensity on baseline CT scan.19
The risk of sICH might also be higher
in patients with cerebral microbleeds,
although this association is not entirely
certain.20
When sudden neurologic decline
occurs during rtPA infusion, the infu-
sion should be immediately stopped
and a CT scan should be obtained
emergently. Whenever postthrom-
bolysis sICH is diagnosed, treatment
tolic target 140 mm Hg to 160 mm Hg)
and reversal of the fibrinolytic effect
with cryoprecipitate (10 units) or an
antifibrinolytic agent (tranexamic acid
10 mg/kg to 15 mg/kg IV over 20 minutes
or (-aminocaproic acid 5 g IV followed
by an infusion of 1 g/h if necessary).
Additional cryoprecipitate may be given
if the serum fibrinogen level remains
below 150 mg/dL.21
Orolingual angioedema is a rare but
potentially serious complication of
rtPA administration. The risk is higher
in patients previously taking angiotensin-
converting enzyme inhibitors. It is typ-
ically asymmetric and tends to involve
the hemiparetic side. The most severe
cases can compromise airway patency;
thus careful monitoring is indispens-
able. Treatment consists of a combina-
tion of diphenhydramine (50 mg IV),
ranitidine (50 mg IV), and dexametha-
sone (10 mg IV).
While IV thrombolysis is the stan-
dard of care for eligible patients with
acute ischemic stroke, this treatment
has limitations. In addition to its short
time window and contraindication in
patients with increased bleeding risk,

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 Acute Ischemic Stroke
IV rtPA often fails to recanalize proxi-
mal artery occlusions caused by large
clots. These are the most disabling
strokes, and strong evidence now
exists that these patients should be
considered for endovascular therapy.
Mechanical Thrombectomy
Although endovascular recanalization
treatment for selected patients with
severe acute ischemic stroke has been
practiced in many centers for decades,
the publication of several recent pos-
itive trials has catapulted this therapy
to the status of evidence-based treat-
ment for patients with large intracra-
nial artery occlusion. Previous trials
had failed to show a benefit from
endovascular therapy because of
suboptimal inclusion criteria (by not
requiring proof of a proximal intracra-
nial artery occlusion before randomi-
zation), longer time to intervention,
and use of less effective reperfusion
devices.22Y24 Instead, the six positive
trials25Y30 shared the requirement of
CT angiogram for patient screen-
ing (only patients with documented
internal carotid artery or proximal
middle cerebral artery occlusions could
be entered into the studies), empha-
sized the importance of prompt inter-
vention, and almost exclusively used
retrievable stents to achieve reper-
fusion, devices that have been solidly
proven to be more effective than
their predecessors.31,32
The main characteristics of the ran-
domized controlled trials establishing
the benefit of mechanical throm-
bectomy are summarized in Table 3-2.
All of them enrolled patients with
severe neurologic deficits and good
prestroke functional status who pres-
ented mostly within 6 hours of symp-
tom onset (Table 3-3). Major early
ischemic changes on the baseline
CT scan were a reason for exclusion.
The great majority of patients in
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KEY POINTS
both arms were treated with IV rtPA. h Six recent randomized
The results were unequivocal: patients controlled trials have
treated with mechanical thrombectomy conclusively proven that
had high rates of reperfusion and endovascular therapy
much better functional outcomes at with mechanical
90 days. thrombectomy improves
When taken in combination, these functional outcomes in
trials demonstrated that between three patients with acute
and seven patients must be treated to stroke from a proximal
help one additional patient regain func- intracranial artery
occlusion (internal
tional independence,33 which is par-
carotid artery, M1 or M2
ticularly remarkable considering the
segments) when the
severity of the symptoms upon pre- intervention is performed
sentation (Case 3-2). Furthermore, within 6 hours of
since the benefit conferred by mechan- symptom onset.
ical thrombectomy spanned through
h Candidates for
the entire range of functional outcome,
endovascular stroke
the number necessary to treat to therapy are patients
reduce disability by one level on the with severe neurologic
modified Rankin Scale was only 2.6. symptoms, no major
This benefit was confirmed across ischemic changes
multiple subgroups (including patients on the baseline CT scan,
older than 80 years and those with very good prestroke
severe strokes as indicated by a base- functional status, and
line NIHSS score higher than 20).33 early presentation.
Mechanical thrombectomy was also h Mechanical
proven to be quite safe, with a pooled thrombectomy can be
rate of sICH of 4.4% across all patients attempted when IV
treated in the intervention arms of thrombolysis does not
the five trials.33 Few emergency treat- result in rapid clinical
ments in medicine have shown this improvement and also
in patients who are
degree of success.
ineligible for IV rtPA.
The dramatic benefit observed in
these trials relied on very high reper-
fusion rates using retrievable stents.
These devices are deployed at the
level of the occlusive clot, capture
the clot in their mesh, and are then
retrieved along with the clot. Inter-
ventions in these trials were prompt
and typically performed by experi-
enced specialists. Delays to treatment
were minimized, and consequently
the times to reperfusion were rela-
tively short. In fact, those trials with
shorter average time to reperfusion
showed the greatest clinical benefit.34
Some unanswered questions still
exist regarding the best application of
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 Acute Ischemic Stroke

TABLE 3-2 Summary of the Main Trials Evaluating Mechanical Thrombectomy With
Retrievable Stents for Acute Ischemic Stroke

Study MR CLEAN25 ESCAPE26 EXTEND-IA27

Size (intervention 500 (233 versus 267) 315 (165 versus 150) 70 (35 versus 35)
versus control)
Age, median (years) 65.8 versus 65.7 71 versus 70 68.6 versus 70.2
a
Time to randomization 6 hours 12 hours 6 hours
Image to puncture
G60 minutes
Clinical selection Any age Any age Any age
NIHSS Q2 Any NIHSS (disabling Any NIHSS
symptoms)
Barthel Index990 Premorbid mRS G2
b
Imaging selection CTA (+/- CTP) CT ASPECTS 6Y10 with good CTA/CTP (core G70 mL)
collaterals 950% of MCA
Any ASPECTS

NIHSS, median 17 versus 18 16 versus 17 17 versus 13

ASPECTS, median 9 9 versus 9 Not reported
IV rtPA, % 87.1 versus 90.6 72.7 versus 78.7 100 versus 100
Onset to groin puncture, 260 185 210
median (minutes)
Onset to reperfusion, Not reported 241 248
median (minutes)
M1 occlusion, % 66.1 versus 62 68.1 versus 71.4 57 versus 51
TICI 2bY3, % 58.7 72.4 86
mRS -0Y2 at 90 days, % 32.6 versus 19.1 53 versus 29.3 71 versus 40
OR 1.7 OR 1.8 OR 4.2
(95% CI 1.2Y2.3) (95% CI 1.4Y2.4) (95% CI 1.4Y12)
mRS 0Y2 at 90 days, NNT 7.1 4.2 3.2
sICH, % 6 versus 5.2 3.6 versus 2.7 0 versus 6
+/- = with or without; ASPECTS = Alberta Stroke Program Early CT Score; CI = confidence interval; CT = computed tomography;
CTA = computed tomography angiography; CTP = computed tomography perfusion; ESCAPE = Endovascular Treatment for Small
Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times; EXTEND-IA = Extending the
Time for Thrombolysis in Emergency Neurological DeficitsVIntra-Arterial; ICA = internal carotid artery; IV= intravenous; MCA = middle cerebral
artery; MR CLEAN = Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands;
MRA = magnetic resonance angiography; mRS = modified Rankin Scale; NIHSS = National Institutes of Health Stroke Scale; NNT = number
needed to treat; OR = odds ratio; REVASCAT = Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy
in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting Within 8 Hours of Symptom Onset;
rtPA = recombinant tissue plasminogen activator; sICH = symptomatic intracerebral hemorrhage; SWIFT PRIME = Solitaire With the Intention
for Thrombectomy as Primary Endovascular Treatment; THRACE = The Contribution of Intra-arterial Thrombectomy in Acute Ischemic
Stroke in Patients Treated With Intravenous Thrombolysis; TICI = thrombolysis in cerebral infarction.
a
84% within 6 hours.
b
67% of MR CLEAN subjects and 81% of SWIFT PRIME subjects had CT perfusion.

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 Acute Ischemic Stroke

SWIFT PRIME28 REVASCAT29 THRACE30

196 (98 versus 98) 206 (103 versus 103) 414 (204 versus 208)

65 versus 66.3 65.7 versus 67.2 66 versus 68

6 hours 3.7 hours 4.5 hours
Image to puncture Onset to groin puncture
G90 minutes 5 hours
Age 18Y80 years Age 18Y80 years Age 18Y80 years
NIHSS Q8 NIHSS Q6 NIHSS 10Y25

Premorbid mRS G2 Premorbid mRS G2

b
CTA (+/- CTP) CTA CTA or MRA

ASPECTS 6Y10 ASPECTS 7Y10 Any ASPECTS

No cervical ICA occlusion
17 versus 17 17 versus 17 18 versus 17
9 versus 9 7 versus 8 Median not reported
100 versus 100 68.0 versus 77.7 100 versus 100
224 269 250

250 355 303

67 versus 77 64.7 versus 64.4 86 versus 79

88 65.7 69
60.2 versus 35.5 43.7 versus 28.2 53 versus 42
OR 1.7 OR 2.1 OR 1.55
(95% CI 1.2Y2.3) (95% CI 1.1Y4.0) (95% CI 1.05Y2.30)
4.0 6.3 9.1
1 versus 3 1.9 versus 1.9 2 versus 2

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 Acute Ischemic Stroke

KEY POINTS
h Careful assessment of pedient method to quantify the extent
brain imaging is TABLE 3-3 Candidates for of early ischemic damage (Figure 3-335).36
necessary to exclude
Acute Endovascular However, the noncontrast CT scan is
Stroke Therapy not sensitive for the visualization of
a large established
infarction (core). early ischemia. One of the trials used
b Age Q18 years multiphase CT angiography to evaluate
h The optimal radiologic
method to select
b NIHSS score Q6 collateral vessels,26 and another re-
candidates for b Time from symptom onset quired a CT perfusion showing a
endovascular therapy is to groin puncture G6 hours limited infarct core and evidence of
not yet established, but b Good prestroke functional penumbra before randomization. 27
the Alberta Stroke status Furthermore, many patients in trials
Programs Early CT that did not require CT perfusion by
b ASPECTS score Q6 on baseline
Score, evaluation of protocol had this imaging before in-
CT scan
collaterals on CT clusion in the study because that was
angiography, and CT b Presence of proximal
the prevailing practice in the enrolling
perfusion or MRI intracranial artery occlusion
center.25,28 CT perfusion can provide
diffusion/perfusion are ASPECTS = Alberta Stroke Program Early
CT Score; CT = computed tomography; more reliable assessment of the is-
all available options.
NIHSS = National Institutes of Health chemic region, but its acquisition re-
Stroke Scale.
quires additional time. MRI diffusion/
perfusion is broadly considered the
most accurate method to determine
mechanical thrombectomy for pa- the ischemic core and the extent of the
tients with acute ischemic stroke. In penumbra, but this technique is less
particular, the best imaging modal- available. New software packages
ity to select patients for the inter- promise to accelerate the time re-
vention remains to be determined. quired to obtain perfusion imaging.
All trials excluded patients with an Yet, at this time, it is unclear if the
Alberta Stroke Program Early CT Score additional time needed to obtain these
(ASPECTS) lower than 6 on baseline images is justified.37 Figure 3-438 illus-
CT scan. The ASPECTS provides an ex- trates the current work flow in the

Case 3-2
A 62-year-old man without past medical history collapsed in his bathroom. The noise alerted his son,
who found his father on the ground, unable to move the right side of his body and mute. He
immediately called an ambulance. Paramedics in the field noted a blood pressure of 180/100 mm Hg
and an irregularly irregular pulse. In the emergency department, the patient had a fluctuating level of
alertness, forced left gaze deviation, a right visual field deficit, global aphasia with mutism, right
hemiplegia, and severe right hypoesthesia. His National Institutes of Health Stroke Scale (NIHSS) score
was 22. Noncontrast head CT scan showed a hyperdense left middle cerebral artery sign, but his
Alberta Stroke Program Early CT Score (ASPECTS) was 10 (Figure 3-2A). CT angiogram showed a flow
gap in the left middle cerebral artery with good collateral flow distal to it (Figure 3-2B). IV
thrombolysis was started 55 minutes after symptom onset, and the patient was taken to the angiographic
suite for endovascular therapy. Groin puncture took place 67 minutes after symptom onset. Initial
injection of contrast into the left internal carotid artery showed that this vessel was occluded at the top of
its supraclinoid segment (Figure 3-2C). Complete recanalization with full reperfusion was rapidly
achieved with mechanical thrombectomy using a retrievable stent (Figure 3-2D). The patient began
improving on the angiographic table and continued to improve overnight. By the next morning, his
NIHSS score was 3. Repeat CT scan showed a small infarction in the left lenticular nucleus (Figure 3-2E).
At 3 months, the patient had full function and no residual symptoms.
Continued on page 74

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 Acute Ischemic Stroke

Continued from page 73

FIGURE 3-2 Imaging of the patient in Case 3-2. A, CT scan of the brain showing hyperdensity in the left middle cerebral
artery consistent with acute thrombus (arrow). B, CT angiogram showing a focal area of left middle cerebral
artery occlusion (arrow) with good collateral flow in the vessels distal to the occlusion. C, Digital subtraction
angiogram demonstrating occlusion of the distal segment of the left internal carotid artery as well as intact collaterals
supplying the peripheral middle cerebral artery branches. D, Full recanalization and reperfusion after mechanical
thrombectomy. E, Repeat CT scan showing a small residual infarction in the left basal ganglia (arrow).

Comment. Thanks to technologic advances, endovascular therapy with mechanical thrombectomy is

highly effective in achieving reperfusion in patients with proximal intracranial artery occlusions. It is
usually combined with IV thrombolysis. However, endovascular recanalization is also beneficial in
patients with contraindications for IV rtPA. Adequate patient selection (in this case, the patient had
no evidence of ischemic changes on CT scan and good collaterals on CT angiogram) and prompt
intervention are crucial to optimize the chances of therapeutic success.

evaluation and treatment of acute is-
chemic stroke.
A growing body of evidence sug-
gests that interventions performed
under conscious sedation have better
outcomes than those performed un-
der general anesthesia. This finding
was first reported in retrospective
studies39 and subsequently confirmed
in a subanalysis of the Multicenter
Randomized Clinical Trial of Endovas- KEY POINT
cular Treatment for Acute Ischemic h Endovascular
Stroke in the Netherlands (MR CLEAN) interventions for acute
stroke should be
trial.40 It is becoming increasingly clear
performed under
that most interventions can be safely conscious sedation
completed using conscious sedation. whenever possible.
An appropriately powered large ran-
domized trial will be necessary to
conclusively determine if conscious
sedation should be preferred over

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 Acute Ischemic Stroke

FIGURE 3-3 The Alberta Stroke Program Early CT Score

(ASPECTS) is designed to quantify the severity
of brain parenchymal changes in acute stroke.
The 10 areas are depicted on this illustration. A normal CT scan
is represented by an ASPECTS of 10. One point is subtracted for
each of the 10 regions when any evidence of early ischemic
change exists. Thus, the lower the ASPECTS, the larger the
extent of the ischemic damage.
Reprinted from Puetz V, et al, Int J Stroke.35 B 2009 World Stroke Organization.
wso.sagepub.com/content/4/5/354.abstract.

FIGURE 3-4 Graphic illustrating the sequence of steps in contemporary acute stroke therapy. IV thrombolysis should be given to
all patients without contraindications within 60 minutes of their arrival to the emergency department. The use of
perfusion imaging is considered optional at this time. Ideally, the time from the qualifying scan to the groin
puncture in candidates for endovascular therapy should be shorter than 60 minutes.
CT = computed tomography; DSA = digital subtraction angiography; IV = intravenous; rtPA = recombinant tissue plasminogen activator.
Reprinted with permission from Rabinstein AA, Nat Rev Neurol.38 B 2016 Alejandro A. Rabinstein. nature.com/nrneurol/journal/v12/n2/full/nrneurol.2015.241.html.

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 Acute Ischemic Stroke
general anesthesia during endovascular
stroke therapy.
Perhaps the main question is
whether the outcomes observed in
the randomized trials can be repli-
cated in daily practice. To achieve this
goal, triaging mechanisms must be
refined and expertise must become
more readily available. Organization
and implementation of stroke net-
works around comprehensive stroke
centers with 24/7 neurointerventional
capability must become a priority. In
turn, neurointerventional centers will
have to prove compliance with strict
metrics of efficiency and safety.
SPECIAL SITUATIONS
Special clinical situations remain for
which the evidence is insufficient to
determine the best course of action.
Until more definite data become avail-
able, these cases should be approached
considering individual factors and what
is known from collective experience.
Wake-up Strokes
Patients whose neurologic deficits are
first noticed upon their awakening
represent a particular challenge to
the clinician. The same applies to
those with unclear time of onset (such
as when the patient is aphasic and the
onset of symptoms was not witnessed).
These situations constitute formal con-
traindications for IV rtPA, but it is widely
agreed that some of these patients may
benefit from reperfusion therapy. When
the baseline CT scan shows no evidence
of a large established infarction, it is
likely that advanced imaging with CT
perfusion or MR diffusion/perfusion
may identify those patients who can be
safely treated and can improve after
successful recanalization (Case 3-3).
Observational studies support this ap-
proach,41,42 which is currently being
tested in the DWI or CTP Assess-
ment With Clinical Mismatch in the
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KEY POINTS
Triage of Wake-Up and Late Presenting h Patients with wake-up
Strokes Undergoing Neurointervention strokes and those with
(DAWN),43 PerfusiOn Imaging Selec- stroke of unknown time
tion of Ischemic STroke Patients for of onset might benefit
EndoVascular ThErapy (POSITIVE),44 from acute reperfusion
Diffusion and Perfusion Imaging Eval- if a large infarct core can
uation for Understanding Stroke Evo- be reliably excluded.
lution 3 (DEFUSE 3),45 and A Phase IIa h It is prudent not to
Safety Study of Intravenous Thrombol- administer IV thrombolysis
ysis With Alteplase in MRI-Selected in patients taking the
Patients (MR WITNESS)46 trials. novel oral anticoagulants
(dabigatran, rivaroxaban,
Intravenous Thrombolysis apixaban, edoxaban)
in Patients Taking because readily available
Newer Anticoagulants tests in the emergency
department cannot
IV rtPA can be administered within quantify the degree of
3 hours of symptom onset to patients active anticoagulation.
taking warfarin whose international
normalized ratio (INR) is 1.7 or less.
However, no adequate safety data
with the newer anticoagulants (the
direct thrombin inhibitor dabigatran
and the factor Xa inhibitors riva-
roxaban, apixaban, and edoxaban)
exist. Readily available laboratory stud-
ies cannot quantify the degree of anti-
coagulation. Thus, it is most prudent
to withhold thrombolysis in patients
taking these agents.12 However, patients
with proximal intracranial artery occlu-
sion may benefit from mechanical
thrombectomy.
Minor and Rapidly
Improving Deficits
Although thrombolysis is often with-
held because the symptoms are
considered mild or patients appear
to be rapidly improving, several ob-
servational studies have shown that
up to one-third of patients who are
otherwise eligible for thrombolysis
but do not receive it for these reasons
are disabled at 3 months.47 Thus, one
must be very careful when assess-
ing these patients. IV rtPA might be
justified when the NIHSS score is low
but the symptoms are nonetheless dis-
abling for the patient (eg, hemianopia
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 Acute Ischemic Stroke

Case 3-3
A 74-year-old woman with a history of atrial fibrillation on aspirin woke up with speech difficulties
and right-sided weakness. She was feeling well when she had gone to bed the night before. Her
husband called an ambulance, and upon arrival to the emergency department, she had a National
Institutes of Health Stroke Scale (NIHSS) score of 15. CT scan of the brain was unremarkable, but CT
angiogram showed occlusion of the left middle cerebral artery with good collateral flow (Figure 3-5A).
CT perfusion demonstrated a large mismatch between the cerebral blood flow (Figure 3-5B) and
the cerebral blood volume (Figure 3-5C) throughout the entire left middle cerebral artery territory.
Consequently, the patient was taken to the angiographic suite and underwent successful recanalization
of the left middle cerebral artery by means of a retrievable stent (Figures 3-5D and 3-5E). She experienced
great clinical improvement over the subsequent 3 days. Follow-up CT scan is shown in Figure 3-5F. At
3 months, she had regained full function.

FIGURE 3-5 Imaging of the patient in Case 3-3. A, CT angiogram showing occlusion of the left middle cerebral artery (arrow);
collateral flow distal to the occlusion was satisfactory. B, Cerebral blood flow image of the CT perfusion
disclosing hypoperfusion throughout the left middle cerebral artery distribution. C, Cerebral blood volume
image of the CT perfusion showing no definite areas of established infarction. D, Digital subtraction angiogram confirming
the presence of an occlusive/subocclusive clot in the proximal left middle cerebral artery. E, Angiographic run after full
reperfusion following treatment with a retrievable stent. F, On follow-up CT scan 24 hours later, a relatively small infarction in
comparison with the initial region of hypoperfusion in the left basal ganglia and internal capsule is seen (arrow).

Comment. Wake-up strokes and strokes of unclear time of onset are particularly problematic because
these cases were not included in the trials supporting IV thrombolysis or mechanical thrombectomy.
Yet, patients with small infarct core and large penumbra can be good candidates for acute reperfusion
therapy. This is one of the situations in which the use of penumbral imaging (CT perfusion or MR
diffusion/perfusion) can be invaluable to identify good candidates for treatment. Ongoing trials should
be able to establish the best strategy for treatment of stroke with uncertain time of onset.

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 Acute Ischemic Stroke
in a professional driver). Improving
deficits that are still disabling at the time
of the neurologic evaluation may simi-
larly warrant thrombolysis. The value of
IV rtPA within 3 hours of symptom
onset in patients with mild (NIHSS
score of 5 or less) or rapidly improving
deficits is being investigated in the
Phase IIIB, Double-Blind, Multicenter
Study to Evaluate the Efficacy and Safety
of Alteplase in Patients With Mild Stroke:
Rapidly Improving Symptoms and Neu-
rologic Deficits (PRISMS) trial.48
Posterior Circulation Strokes
Randomized trials of IV thrombolysis
and mechanical thrombectomy (ex-
cept for very few patients enrolled
in The Contribution of Intra-arterial
Thrombectomy in Acute Ischemic
Stroke in Patients Treated With Intra-
venous Thrombolysis [THRACE] trial)30
have been restricted to patients
with anterior circulation strokes. Yet,
clinical experience with treating pos-
terior circulation infarctions with these
therapies exists. Basilar artery occlu-
sions can be devastating unless recan-
alization is achieved. Registry data
indicate that IV rtPA49 and mechanical
thrombectomy50 can result in func-
tional independence at 3 months in
30% to 40% of cases; these rates of
favorable outcome are clearly greater
than those reported without reper-
fusion therapy.51 The value of endo-
vascular therapy for acute basilar
occlusion is currently being investi-
gated in the Basilar Artery International
Cooperation Study (BASICS).52 Even
among patients who are treated with
reperfusion strategies, mortality re-
mains high (30% to 35%).49,50 There-
fore, many consider extending the
therapeutic window for IV thromboly-
sis beyond 4.5 hours and for mechan-
ical thrombectomy far beyond 6 hours
in patients with basilar artery occlusion
who do not have a large established
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KEY POINTS
pontine or cerebellar infarction to be h Patients with mild or
reasonable. rapidly improving
strokes who present
FUTURE DIRECTIONS within the time window
Current efforts are focused on increas- for IV thrombolysis and
ing the efficiency of systems of care and still have disabling
investigating new strategies for acute symptoms at the time of
stroke therapy. The common objective the evaluation should
is to increase the number of patients probably be offered
with acute ischemic stroke who can treatment with rtPA.
regain perfusion of the ischemic tissue h Although patients with
before infarction is established. basilar artery occlusion
Mobile stroke units are rapidly were not included in the
gaining acceptance. These are special randomized controlled
ambulances equipped with a portable trials of IV thrombolysis
or mechanical
CT scanner and digital technology to
thrombectomy, these
enable telecommunication with a
patients should be
stroke specialist. They have been shown
treated with acute
to allow safe initiation of IV throm- reperfusion therapies
bolysis while en route to the stroke because of their dismal
center.53 This option, although expen- prognosis if recanalization
sive, can be a very welcome solution cannot be achieved.
for some heavily populated urban com- h Mobile stroke units have
munities. Dispatchers and paramedics been shown to provide
must receive specific stroke education a safe way to start
to optimize the efficiency and safety of thrombolysis in the
these mobile units. prehospital setting.
Ways to extend the therapeutic win-
dow (beyond 4.5 hours for IV therapy
and 6 hours for mechanical thrombec-
tomy) are being actively investigated.
Using more fibrin-specific fibrinolytic
agents has been considered a promis-
ing option for years. Trials using
desmoteplase showed no benefit,54
but tenecteplase is still being studied.55
Radiologic identification of patients
with better collateral flow resulting
in persistently salvageable tissue is
broadly considered a reasonable,
albeit still unproven, approach. Se-
lection of candidates using perfusion
imaging modalities is being tested in
ongoing trials (DAWN, DEFUSE 3, and
MR WITNESS).43,45,46
Collateral flow augmentation is an-
other proposed strategy. In current
practice, this is sometimes attempted
with vasopressors. Evidence is restricted
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 Acute Ischemic Stroke
to small case series and one pilot
feasibility study.56 Yet, hemodynamic
augmentation with vasopressors can
occasionally work, in particular in pa-
tients with proximal vessel occlusions
who are not deemed candidates for
endovascular recanalization or in
whom the recanalization attempt was
unsuccessful. Mechanical techniques
for collateral recruitment (such as ex-
ternal counterpulsation and intraaortic
inflation devices) have been shown
feasible and safe, but their efficacy
remains to be proven.57
The evolution of emergency treat-
ment for acute ST-segment elevation
myocardial infarction can inform the
future of acute stroke therapy from a
proximal artery occlusion. Fibrinolysis
followed by endovascular therapy was
initially a common practice but was
later abandoned after randomized tri-
als demonstrated that proceeding di-
rectly to the endovascular intervention
was a superior strategy. Once systems
of care are optimized to guarantee fast
access to the angiographic suite for
patients with acute stroke, it will be
necessary to perform a trial comparing
IV thrombolysis followed by mechan-
ical thrombectomy versus primary
mechanical thrombectomy for patients
with severe stroke and proven proximal
artery occlusion.
CONCLUSION
Acute ischemic stroke is a medical
emergency in which every minute
counts. Achievement of reperfusion
can reverse neurologic deficits, even
if severe, and allow patients to regain
function. Two reperfusion strategies
are now proven: IV rtPA and mechan-
ical thrombectomy. They are both safe
and effective for the right candidates.
Patient selection is crucial to optimize
outcomes, but the attitude of the
clinician should be that treatment
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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
should be given unless a solid contra-
indication exists.
At this juncture, efforts should be
concentrated on refining systems of
care to allow more patients to have
access to reperfusion treatment. Ex-
panding the number of candidates for
intervention will require continuous
education of the community to recog-
nize signs of stroke, improving the
initial triage of patients with stroke,
and speeding evaluation and treat-
ment in the hospital. Ongoing trials
are also evaluating the possibility of
extending the therapeutic window by
using advanced imaging modalities to
identify patients in whom good collat-
erals have preserved tissue viability for
a longer time. Collateral augmentation
strategies and ultra-early administra-
tion of neuroprotective agents may
provide additional treatment venues
in the future.
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