NEUROLOGY GRAND ROUNDS

Challenges and Opportunities of

Endovascular Stroke Therapy
Mayank Goyal, MD,1 Michael D. Hill, MD,1,2 Jeffrey L. Saver, MD,3 and
Marc Fisher, MD4
In light of the results of the recent trials comparing endovascular treatment for acute ischemic stroke compared to
the previous standard of care, endovascular treatment is now the new standard for patients with acute ischemic
stroke resulting from proximal vessel occlusion. This is probably the greatest advancement in stroke treatment in two
decades. However, these results, in addition to creating great opportunities for better outcomes for stroke patients
and for future research, have also brought with it new challenges. In this article, we present the key results of the trials, as well as future challenges and opportunities.
ANN NEUROL 2016;79:1117

Endovascular Stroke Treatment Principles

mong the two types of stroke, ischemic and hemorrhagic, ischemia is the most common (85% of all
strokes) and ranges in clinical severity from transient
ischemic attack and minor stroke to severe and deadly
resulting from large, proximal vessel occlusion. Anterior
circulation occlusion of the middle cerebral artery stem
with or without occlusion of the top of the internal
carotid artery, typically resulting from an embolus from
the heart or a carotid artery bifurcation atherosclerotic
plaque, is commonest. Fast neurovascular imaging with
brain computed tomography (CT) and CT angiography
(CTA) from aortic arch to vertex is critical for diagnosis
and immediate treatment planning. Severe strokes make
up as much as one quarter of all strokes (200,000
patients annually in North America) and 30-day mortality in this group is approximately 20%.1 Only half of
stroke victims get to the hospital in time for standard
intravenous thrombolysis with alteplase,2 and when a
large proximal intracranial artery is occluded, alteplase
results in early nutritive reperfusion only one third of the
time.3

Recent data from five randomized, controlled trials

published in the journal provide clear evidence that
among patients with acute ischemic stroke due to large
vessel anterior circulation occlusion endovascular treatment using stent retrievers (with or without tissue plasminogen activator [tPA]) dramatically improves patient
outcome.37 This is the greatest advance in acute stroke
treatment in 20 years. Treatment was effective and safe
across many different countries, jurisdictions, and health
care systems. The effect size was large and consistent
across all five studies, showing a shift to lower rates of
disability and death on the modified Rankin Scale (mRS;
common odds ratio range: 1.73.1) and with an absolute
risk benefit of 13% to 31% in the proportion of patients
achieving an independent functional outcome at 90 days.
There are significant immediate health care implications
and future possibilities that arise from these findings.
Key similarities among the five trials were the confirmation of a proximal vascular occlusion, predominantly with CTA, the inclusion of severe strokes, a
similar age range, and fast treatment by a stroke neurology and neurointervention team with a stent retriever

View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.24528

Received Jun 18, 2015, and in revised form Sep 11, 2015. Accepted for publication Sep 18, 2015.
Address correspondence to: Mayank Goyal, Department of Radiology, Seaman Family MR Research Center, Foothills Hospital, 1403 29th Street Northwest, Calgary, Alberta, Canada, T2N2T9. E-mail:mgoyal@ucalgary.ca
From the 1Department of Radiology and Clinical Neurosciences, Foothills Hospital, Cuming School of Medicine, University of Calgary, Calgary, Alberta,
Canada; 2Department of Community Health Sciences and Medicine, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary,
Calgary, Alberta, Canada; 3Geffen School of Medicine at UCLA, UCLA Comprehensive Stroke Center, Los Angeles, CA; and 4Department of Neurology,
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA

C 2015 American Neurological Association

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initiated within 6 hours from stroke onset in most

patients. A majority (73100%) were treated concurrently with intravenous alteplase, with onset-toreperfusion times within 4 hours and with complete or
near complete reperfusion in a large percentage of
patients (Table). Important differences were the use of
penumbral imaging using CT perfusion technology or
intracranial collateral imaging using multiphase CTA
(mCTA), and the explicit focus on improving workflow
metrics within the trials. The two trials that reported
slower workflow metrics did not demonstrate as large an
effect size. In one trial, there was a protocol-defined
period of 30 minutes after intravenous tPA treatment to
establish that patients had not reperfused with intravenous tPA before enrollment. The trial with the fastest
imaging to reperfusion times showed a mortality benefit.
The common themes from all trials were: (1)
patient selection using brain CT and neurovascular imaging; (2) fast and early treatment; and (3) complete or
near complete reperfusion. All the trials used imaging to
confirm the presence of an acute ischemic stroke (and to
rule out hemorrhage or other stroke mimics) and confirm the presence of a target lesion for endovascular
treatment: a proximal vessel occlusion (M1 segment of
the middle cerebral artery [MCA] with or without intracranial internal carotid artery occlusion). Four of the trials (all except for MR CLEAN) used imaging to exclude
patients with well-established regions of large ischemic
coreregions that have already progressed to, or will
progress to, irreversible infarction despite treatment. CT
was used in almost all of the patients because of clear
advantages of availability, access, and relative lack of contraindications when compared with magnetic resonance
imaging (MRI).
A noncontrast CT head, followed immediately by a
CTA from aortic arch-to-vertexbased imaging paradigm
is highly effective in making an inclusive diagnosis of
ischemic stroke, confirming the presence of an endovascular target proximal vessel occlusion and defining the
great vessel anatomy for procedural planning. With
attention to the quality of CT acquisition parameters,
very-high-quality brain imaging is available. In the
ESCAPE trial and in a minority of patients in the
REVASCAT trials, a novel technique termed mCTA was
introduced to view and measure the intracranial collateral
circulation.8 This technique can be performed with no
additional contrast, is inexpensive, very fast, adds negligible additional radiation exposure, is less vulnerable to
patient motion than CT perfusion imaging, and does not
require complex postprocessing. Use of the ASPECTS
score and collateral imaging to exclude patients with
large cores and poor collaterals was an effective, time12

efficient imaging paradigm. CT perfusion imaging was

used in EXTEND-IA and a majority of patients in the
SWIFT PRIME trial. An automated postprocessing
method was used to improve efficiency with a priori
thresholds to determine ischemic core and penumbra.9
There remains debate over the precise computed tomography perfusion (CTP) thresholds for patient selection. It
is quite likely that there will be no precise thresholds
given that the thresholds for defining the ischemic core
and penumbra will be dependent on the speed of
recanalization.10
An estimated 1.9 million neurons and 12km of
axons are lost every minute during a MCA occlusion11;
the more rapidly reperfusion is accomplished, the greater
the degree of tissue salvage and the better the clinical
outcome.1214 Most patients treated in the current trials
were treated early after stroke onset (within the first 6
hours). Some of the trials set aggressive time metrics for
workflow (ESCAPE: start of CT imaging to groin puncture <60 minutes; start of CT imaging to first reperfusion <90 min; SWIFT PRIME: qualifying imaging to
groin puncture <70 min) and successfully met these metrics with aggressive training, continuous feedback, and
quality improvement throughout the trial. Replication of
the trial outcomes in clinical routine practice will require
these kinds of rapid treatment times.15
Biologically, the procedural goal is to open the
occluded vessel without complication, achieving complete
or near complete reperfusion defined as Thrombolysis In
Cerebral Ischemia (TICI) 2b or 3 flow.16,17 Patients with
TICI 3 reperfusion (completely normal angiogram) have
the best outcomes. Intracranial complications can include
vessel perforation leading to subarachnoid hemorrhage or
intracerebral hemorrhage (ICH), and embolization of
fragmented thrombus into the distal circulation. Stent
retrievers were the most commonly used devices in these
trials and showed a high degree of efficacy in achieving
reperfusion (TICI 2b/3 range: 5888%) with exceedingly
low procedural complications.

Challenges of Implementing the Trial

Results Into Routine Clinical Practice:
The 5Ts
The chain of survival for successful endovascular stroke
treatment needs to be highly efficient (Figure). It is and
will be a challenging problem of logistics, teamwork, and
technology to organize regional systems of care to implement this therapy.
Transport
Regionalized systems of care must route appropriate
patients for endovascular therapy to centers that can
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TABLE 1. Characteristics, Metrics, and Outcomes of the Five Recent Endovascular Trials

Trial

Patients

NIHSS (median)

IV tPA (%)

Onset-toGroin
Puncture
(minutes,
median)

CT-toGroin
Puncture
(minutes,
median)

Patient characteristics
Endo

Ctrl

Endo

Ctrl

Endo

Ctrl

Endo only

Endo only

MR CLEAN

237

267

17

18

91

87

260

ESCAPE

165

150

16

17

73

79

200

51

REVASCAT

103

103

17

17

100

100

269

77

SWIFT PRIME

98

98

17

17

100

100

224

57

EXTEND IA

35

35

17

13

68

78

210

93

Outcomes
% favorable
reperfusion
MR CLEAN

% mRS 02

% mortality

% symptomatic ICHc

Endo

Ctrl

Endo

Ctrl

Endo

Ctrl

Endo

Ctrl

59

33

19

21

22

6.0

5.2

3.6

2.7

ESCAPE

72

31

53

29

10

19

REVASCAT

66

44

28

18

16

1.9

1.9

SWIFT PRIME

88

60

36

12

3.0

EXTEND IA

86

71

40

20

6.0

MR CLEAN: Multicenter randomized, clinical trial of endovascular treatment for acute ischemic stroke in the Netherlands trial;
ESCAPE: Endovascular treatment for small core and anterior circulation proximal occlusion with emphasis on minimizing CT to
recanalization times trial; 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 present within eight hours of symptom onset;
SWIFT-PRIME: Solitaire with the intention for thrombectomy as primary endovascular treatment trial; EXTEND IA: Extending
the time for thrombolysis in emergency neurological deficits-intra-arterial trial.
Endo: Endovascular therapy was 100% stent retrievers in EXTEND-IA, SWIFT PRIME, and REVASCAT, 97% in MR CLEAN,
and 86% in ESCAPE.
Control: this was tPA in all patients in some trials and the majority of patients received tPA in the other trials.
NIHSS 5 National Institutes of Health Stroke Score; tPA 5 tissue plasminogen activator; CT 5 computed tomography;
mRS 5 modified Rankin Scale; ICH 5 intracerebral hemorrhage; TICI 5 Thrombolysis In Cerebral Ischemia.
% favorable reperfusion: a TICI 2b/3 score on follow-up imaging indicating 50% to 100% reperfusion.
Dash indicates not reported in the primary manuscript.
a
Statistically significant difference in mortality with endovascular therapy.
b
Determined by CT angiogram 2 to 8 hours after randomization.
c
As reported in the primary article. PH2 definition used where reported.

perform it as quickly as possible. Training of and tools

for paramedics to determine which patients have a high
likelihood of an acute ischemic stroke diagnosis resulting
from a proximal vessel occlusion are available. Validated
scoring systems (e.g., Los Angeles Motor Score; LAMS)
already exist, but will likely need to be improved.18 Policy may need to be changed. Telemedicine and video
conferencing between paramedics and physicians and
even patients or their family member and physicians,
now possible with smart phones but obstructed by priJanuary 2016

vacy policy, could help in timely decision making. Local

geography, weather, and traffic patterns can be incorporated into transportation optimization algorithms using
geographical information systems (GIS), and effective
communication systems could help optimize decision
making on the route and modality of transportation.
Agreements will need to be made on the destination hospitals in a given region. It is highly likely that
there exists a volume outcome relationship between
endovascular treatment and favorable stroke outcomes.
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FIGURE 1: Flow chart demonstrating sequence of events and strategies to improve workflow. ER 5 emergency room;
ABCs 5 airway, breathing, circulation; IV 5 intravenous; mCTA 5 multiphase computed tomography angiography; CTP 5 computed tomography perfusion; CT 5 computed tomography; NIHSS 5 National Institutes of Health Stroke Score; tPA 5 tissue
plasminogen activator.

The destination hospital must have a team in place that

can deliver the treatment fast and well. Once the possible
destination hospitals are known, the GIS-enabled communication system can help to determine whether a
direct to comprehensive stroke center or a drip-and-ship
approach is optimal. Such decision algorithms will
depend upon the stroke severity, probability of a large
vessel occlusion as a target for endovascular therapy, the
probability of early reperfusion with intravenous tPA,
distances to both a primary stroke center and to a com14

prehensive stroke center, traffic, weathe,r and available

modality of transportation. In particular, the drip and
ship paradigm will necessitate an extreme effort to minimize the time in the primary hospital; indeed, ideally the
patient is never actually moved off the paramedic
stretcher going from the emergency department door to
the CT scanner, receiving intravenous tPA in the scanner,
and immediately leaving the primary hospital for the
comprehensive stroke center. In the future, mobile stroke
ambulances with built-in CT scanners and aided by
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telemedicine consultation may allow even more sophisticated triage decisions to be made in the field.19 Given
the efficacy of the treatment, it is critical that there be a
strong collective effort to get the correct patient to the
correct hospital to be treated by the correct team in the
most efficient fashion.
Teamwork
All the current trials were performed at centers with
experienced endovascular teams and well-established
processes to allow not only patient evaluation and imaging, but also safe and fast endovascular management
using modern devices. The endovascular management of
acute stroke is a team sport that requires interaction and
cooperation among multiple physicians, allied health professionals, technicians, and hospital administrators.20
There is a need both for resources to organize these
teams and also the creation of hospital cultures of teamwork. National and local guidelines will evolve to define
the standard-of-care and workflow metrics for team organization and delivery of endovascular acute stroke therapy. Accreditation standards must include and recognize
the need for this kind of teamwork.
Technology
This new standard of care will spark an entire new cycle
of innovation to further improve the available technology
for performing acute stroke interventions. Device
improvements to safely increase the effective reperfusion
rate and to improve fast access to the intracranial circulation are needed. Technological advances and innovation
will not be limited to neurointervention devices. New
technologies may help in decision making regarding triage and transportation. There is an evolving small group
examining the use of CT-equipped ambulances19; further
miniaturization of CT may be possible. New understanding of stroke imaging and automation of algorithms for
image processing will lead to refinement or patient selection and better resource use. Endovascular patient simulators are needed to aid in training.
Training and Technique
The success of any interventional procedure is a combination of appropriate technology and the skill of the
operator. In endovascular stroke treatment, there is the
added challenge of working against time and upon a relatively sick and uncooperative patient. As a disease dominantly of the elderly, tortuosity of the blood vessels,
presence of stenosis along the access pathway resulting
from atherosclerotic disease, and presence of other
comorbidities introduce technical challenges. Finally, the
intracranial circulation is fragile; it is unsupported by
January 2016

strong fibrous tissue or fascia as elsewhere in the body

and instead rests in the delicate pia arachnoid.
The current trials were limited to a few highvolume centers with proven expertise. To spread the benefit of this treatment, there is a need for additional qualified centers with additional trained personnel. The
penetration of this treatment to some of the most populous parts of the world where the incidence of stroke is
high is still in its infancy. The need for training in neurointervention will be aided by patient simulators. Training of residents and fellows is impacted by the need for
efficiency where the staff neurointerventionist is limited
in providing adequate training opportunities owing to
the focus on efficiency, that is, the need to open the
occluded vessel as quickly as possible. Though neurointervention training will build upon a base of intracranial
aneurysm treatment, it must be expanded and improved
to deal with the realities of treating awake patients at
speed to replicate and further improve outcome compared to the current trials. The use of simulation has
great potential in exposing trainees to the real-life challenging scenarios in a practice environment. Finally,
training guidelines will need to be adapted to define
what constitutes adequate training,
Training is not limited to the actual neurointervention procedure, but includes all aspects of stroke patient
care from prehospital evaluation and transport, acute
neurological evaluation, and treatment and neurocritical
care management of the patient after successful reperfusion. We hope and recommend that professional societies, hospitals, and accreditation bodies allocate
sufficient time and resources for improved training and
certification along the entire chain of acute stroke care.

Immediate Opportunities: Whats Next?

The success of recent trials has shown the commitment
of all components of the stroke community to work
toward the common goal of providing definitive evidence
in support of a new treatment. This commitment,
momentum, and cooperation can be used to answer
ongoing related questions related to maximizing the benefits of acute stroke therapy. Many clear questions arise
as natural extensions of the inclusion/exclusion criteria of
the recent trials: (1) Does acute ischemic stroke resulting
from M2 (second-order branch) branch of MCA occlusion also benefit from endovascular treatment?; (2) Can
the results of the current trials be extrapolated to the posterior circulation, pediatric populations, and patients in
later time windows beyond 6 hours from stroke onset
with a favorable imaging profile?; (3) In a patient undergoing endovascular treatment, is intravenous alteplase
necessary?; and (4) What imaging and/or clinical criteria
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define absence of benefit (or potentially even harm) such

that endovascular treatment should not be offered? For
example, what is the lower limit of the CT ASPECTS
score or upper limit of the ischemic core volume on CT
perfusion where endovascular therapy is no longer effective? Trials and pooled analyses are being designed that
will soon be underway to answer many of these
questions.

The Future: The Human Focal

Ischemia-Reperfusion Model
We now have a focal ischemia-reperfusion MCA occlusion model in humans. This is the very model that has
been so extensively explored in the preclinical setting.21,22
The human model was lacking at the time many of the
previous neuroprotection drugs were undergoing clinical
testing. Similarly, studies of stroke imaging using MRI or
multimodal CT to assess imaging predictors of tissue fate
have been confounded by a lack of reperfusion in a substantial proportion of patients. There is now a very exciting opportunity to reassess what exactly acute imaging
means, to provide definitive guidance to clinicians making treatment decisions. Even more enticing is the opportunity to re-explore adjuvant treatments for stroke.
We envision a rebirth of pharmacological stroke
treatment in which a neuroprotective agent can be used
to prevent infarct growth until the vessel is being opened
using endovascular thrombectomy. Even more exciting
would be the possibility that such an agent could be
administered in the field or in the ambulance by paramedics. Such a drug would slow the trajectory of infarction such that the proportion of patients who arrive at
the comprehensive stroke with a favorable imaging profile would rise dramatically, thereby increasing the number of patients who could benefit from fast reperfusion
therapies. In stroke animal models, it has been observed
that neuroprotective drugs or gases could slow down or
stop the evolution of the ischemic core for several
hours.2325 If this was feasible in humans, many patients
who now could not get to an endovascular center in time
would become appropriate candidates for this highly
effective therapy. The implementation success of the
FAST-MAG trial, with a median onset-to-treatment time
of 45 minutes, shows the feasibility of such an approach
to prehospital neuroprotective treatment.26 Neuroprotective agents given after reperfusion was achieved could target multiple mechanisms including reperfusion injury,
bloodbrain barrier breakdown, and hemorrhage risk.
It is an exciting time in the world of acute ischemic
stroke with dramatic recent advances and boundless
opportunities for further progress in the near future.
There is much to be done to build upon the recent suc16

cesses to maximize outcomes in as many patients as possible. Time is brain.

Author Contributions
M.G. came up with the idea and wrote the first draft.
M.D.H., J.L.S., and M.F. provided critical input and
revisions to the document. All authors had complete
access to the final version and have approved it.

Potential Conflicts of Interest

Dr Hill was one of the PIs of the ESCAPE trial. Dr
Saver was one of the PIs for the SWIFT PRIME trial.
Dr Goyal is one of the PIs of ESCAPE and SWIFT
PRIME. ESCAPE was partially funded by Covidien
through a grant to the University of Calgary. SWIFT
PRIME was fully funded by Covidien. Dr Goyal has a
consulting agreement with Covidien to assist with design
and conduct of the trial and also for teaching engagements. Dr Goyal has a patent (pending) regarding methods for diagnosing (licensed to GE Healthcare) and a
patent (pending) related to packaging for stroke intervention to improve efficiency. Dr Saver is an employee of
the University of California. The University of California
(UC) Regents receive funding for Dr Savers services as a
scientific consultant regarding trial design and conduct to
Medtronic/Covidien, Stryker, Neuravia, BrainsGate,
Pfizer, Squibb, Boehringer Ingelheim (prevention only),
ZZ Biotech, and St. Jude Medical. Dr Saver has served
as an unpaid site investigator in multicenter trials run by
Lundbeck for which the UC Regents received payments
on the basis of clinical trial contracts for the number of
subjects enrolled. Dr Saver serves as an unpaid consultant
to Genentech advising on the design and conduct of the
PRISMS trial; neither the UC nor Dr Saver received any
payments for this voluntary service. The UC has patent
rights in retrieval devices for stroke.

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