Dr. Brook and Dr. Miller are at Albert Einstein College of Medicine in Bronx, NY. Mr. Levitt is at Case Western Reserve University, Cleveland, OH.
The science of stroke prevention has made significant strides over
the last decade, with an increasing prevalence of statin and
antiplatelet usage, as well as a better ability to control the
deleterious effects of hypertension. Unfortunately, not all patients are
fortunate enough to receive the “best medical therapy.” Therefore,
physicians need to be aggressive in early intervention, attempting to
reverse the natural history of acute stroke. This will only be
accomplished with multidisciplinary teams and focused research to
determine which patients will benefit most, with the least risk. The aim
of this review is to bring to light the options and criteria that are
relevant today and what areas we need to further elucidate with
In its simplest form, an ischemic stroke occurs
when a region of the brain does not receive adequate blood supply for a
time period sufficient to cause cell death. All current methods approved
by the United States Food and Drug Administration (FDA) to treat acute
ischemic stroke are intended to restore blood flow to underperfused
brain tissue by opening occluded vessels within a well-defined time
period or ‘window.’ To understand the emerging role for endovascular
therapy in the management of acute stroke, a historical perspective is
needed as outlined chronologically in Table 1.
was considered standard management for acute stroke until the landmark
National Institute of Neurologic Disease and Stroke (NINDS) trial was
completed in 1995.1 Based on the risk/benefit profile
demonstrated by this study, the FDA granted approval for the use of IV
thrombolysis with tPA within 3 hours of symptom onset. The treatment
window was extended to
4.5 hours as a result of the European Cooperative Acute Stroke Study
(ECASS) III trial completed in 2008.2
Endovascular treatments date to the 1950s, when Sussman and Fitch first pioneered intra-arterial (IA) thrombolysis.3
In the 1990s, numerous prospective observational studies of this
approach were conducted, resulting in several meta-analyses in the
2000s.4 Compared to anticoagulation with heparin, these
studies showed improved outcomes, but there were higher incidences of
symptomatic intracranial hemorrhage (SICH). These claims were further
substantiated in the prospective randomized control trials Prolyse in
Acute Cerebral Thromboembolism (PROACT) I and II, demonstrating some of
the most beneficial outcomes of any stroke trial to date, despite most
of their patients presenting outside of the 4.5-hour period.5 Although
the risk/benefit profile was similar to that of the NINDS trial, the
FDA did not grant a label to IA thrombolysis for the treatment of acute
Emerging role for endovascular treatments
IV thrombolysis is regarded as the current standard of care, there are
many limitations, based on original NINDS criteria, with respect to whom
can be treated. Fewer than 4% of all stroke patients in the United
States receive thrombolytic therapy.6 This is related to the
numerous contraindications to systemic thrombolysis and the fact that
most patients present to emergency departments (ED) outside of the
appropriate time window.
Intra-arterial mechanical options, which
are perceived to have a lower risk of causing SICH than thrombolytics,
provide the opportunity to treat patients who are excluded from IV
therapy. The Mechanical embolus removal in cerebral ischemia (MERCI)
retriever, designed to remove clots rather than dissolve them, was
patented in 2004 and validated in the MERCI and Multi-MERCI prospective
observational studies.7,8 This led to the FDA’s approval of
the MERCI device for use in acute stroke up to 8 hours after symptom
onset, or within the 3- to 4.5-hour window if IV thrombolysis is
contraindicated (Figure 1). The Penumbra retriever was patented in 2007
and validated in the Penumbra Pivotal Stroke Trial (PPST), a prospective
observational study demonstrating an 81.6% recanalization rate, 25%
favorable outcome at 90 days, and incidence of SICH comparable to the
NINDS IV tPA cohort (Figure 2).9 The discrepancy between the
high rate of recanalization and low rate of favorable functional outcome
in this trial illustrates the importance of proper patient selection
and endovascular technique.10
occlusions (ie, M1, carotid, and basilar arteries) lead to the greatest
morbidity and mortality from stroke, and it has been shown that IV
thrombolysis is less effective in treating such lesions.11
Evidence suggests that endovascular techniques utilized in conjunction
with IV thrombolysis, also known as bridging or combined therapy, may
lead to better patient outcomes when large-caliber vessel occlusions are
present.12 If the results of the prospective randomized
trial Interventional Management of Stroke (IMS) III are consistent with
those from the prospective RECANALISE study, a role for early
utilization of endovascular treatment in acute ischemic stroke when
proximal vessel occlusions would be justified.
have advocated primary angioplasty and stenting, similar to the coronary
standard of care, as a more rapid way of achieving recanalization while
treating an underlying, causative, lesion.13 More recently,
retrievable stents have been developed with the goal of improving the
rate of recanalization, as they are usually deployed prior to
thrombectomy. Recent evidence supports this claim of less time to
recanalization and also shows higher rates of success than previously
reported.14,15 In addition, permanent stents require a
combined antiplatelet regimen that has been shown to add significant
systemic hemorrhage risk.16,17 However, improved functional outcomes at 3 months have yet to be demonstrated.
Established criteria for patient selection
role is emerging for primary endovascular therapy in medium- and
large-artery occlusion. Given the potential for symptomatic
complications, it is important neither to deprive patients of effective
interventions nor to expose them unnecessarily to the interventions’
Initial parameters for patient selection are the criteria used in the 1995 NINDS trial.1
Subsequent analysis of ECASS showed that patients with greater than 33%
hypoattenuation in the middle cerebral artery (MCA) did not benefit
from IV tPA. Moreover, these patients showed a significantly increased
risk for fatal brain hemorrhage.18 The Alberta Early Stroke
Program Computed Tomography (CT) score (ASPECTS), a composite score
reflecting ischemia in 10 sub-regions of the MCA territory, has been
advocated as a similar but more reliable measure of ischemia.19 Perhaps more importantly, magnetic resonance (MR)-based implementation of the > 1/3 MCA and ASPECTS <
7 rules has dramatically increased sensitivity for detecting ischemia
and independently predicts favorable functional outcomes (modified
Rankin Scale (mRS) < 2) as well as SICH.20-22 This
increased sensitivity associated with MR-based diagnosis translates to
improved prognostication and, therefore, better patient selection.
characteristics, such as age, stroke severity, and risk for hemorrhage,
as well as imaging characteristics, such as the presence of hemorrhage
or large volumes of ischemia, represent established criteria that can
guide the decision to institute an attempt at revascularization.
Emerging criteria derived from multimodal imaging are being proposed to
improve patient selection further.
Emerging criteria for patient selection
A patient’s collateral circulation
can maintain perfusion to ischemic brain tissue and keep it viable
despite blockage of the tissue’s proximal blood supply. Multimodal
imaging is being used more frequently to triage acute stroke patients in
an effort to identify those most likely to benefit from reperfusion and
least likely to hemorrhage or progress to malignant edema. Prospective
trials have shown that adding CT angiography (CTA)/CT perfusion (CTP) or
MR imaging/MR angiography (MRA)/MR perfusion (MRP) adds 5 to 10 minutes
for CT and < 30 minutes for MRI without diminishing favorable
The holy grail of patient selection is
identifying brain tissue that is hypoperfused, but not infarcted, and
hence potentially salvageable. The ischemic penumbra is commonly defined
by subtracting the brain region with restricted diffusion from the
region associated with low cerebral blood flow. Diffusion restriction is
expected in an intracellular fluid shift, as there is less freedom for
particles to diffuse relative to the extracellular space. Intracellular
fluid shifts signify failed ATP-dependent Na+/K+ ATPases, which is
consistent with infarcted tissue. Although this perfusion-diffusion
mismatch framework is conceptually appealing, neither the Echoplanar
Imaging Thrombolytic Evaluation Trial (EPITHET) nor the Desmoteplase in
Acute Ischemic Stroke (DIAS) II trial could confirm the favorable
results seen in earlier studies that used perfusion-based criteria for
patient selection.24,25 These studies included patients with
proximal-vessel occlusions treated only with IV therapy. It has
subsequently been shown that these occlusions are successfully
recanalized with IV therapy in only 10% to 30% of patients.26 Patient selection is crucial and may have limited the generalizability of the findings of these studies.
DWI lesion volumes, blood-brain barrier permeability, and relative cerebral blood flow thresholds
on the results of EPITHET and DIAS II, as well as observations of
“benign oligemia,” perfusion-diffusion mismatched tissue remains viable
despite failed recanalization, a more precise characterization of the
penumbra is clearly needed if it is to become clinically useful.26 Other imaging-based criteria are evolving as additions or alternatives to the mismatch concept.
weighted imaging (DWI) lesion volume is one such alternative. It is
based on the premise that stroke patients with sufficiently large
infarcts will have poor outcomes despite a significant
diffusion/perfusion mismatch. Two retrospective studies of patients with
anterior-circulation strokes who had pretreatment MRIs and were treated
with IV or IA thrombolysis identified a DWI lesion volume cut-off with
prognostic value.27,28 These findings are promising and prospective studies have been initiated to validate these results.29
brain barrier permeability (BBBP) measurements, calculated from
pretreatment CT perfusion imaging data, are another example of an
alternative method to stratify patients. A retrospective study of 32
tPA-treated patients demonstrated that, in conjunction with old age
(> 65 years), BBBP measurements can be 100% sensitive for predicting
symptomatic hemorrhagic transformation (SHT) and malignant edema (ME).30
If these results hold up in prospective trials, stroke teams would be
enabled to safely pursue thrombolytic treatments outside of the 3- to
4.5- hour window.
Cerebral blood flow (CBF) thresholds—the points
below which tissue distal to an arterial occlusion would infarct even if
recanalization were successful—have been retrospectively identified.31
It is reasonable that companion CBF thresholds will be identified where
tissue perfusion can be maintained at a level where recanalization is
unnecessary even when a proximal vessel is occluded.
FDA guidelines call for all stroke patients to receive IV tPA within
the 4.5-hour window, but patients are unlikely to benefit from IV
therapy in certain situations. In the setting of a proximal MCA
occlusion and a hyperdense MCA sign (HMCAS) on CT imaging, evidence
suggests a higher likelihood of improved outcome when IA lytics are used
instead of IV therapy alone.32 However, HMCAS sensitivity for MCA territory infarcts is only about 30%.33
Other clot image characteristics can be used to identify patient groups
unlikely to benefit from IV lytics and guide management of stroke
patients without HMCAS (Figure 3). Clot length, as measured by
semi-automated segmentation of thin-slice noncontrast CT scan
reconstructions, may be one such characteristic. A retrospective study
of 138 patients presenting < 3 hrs after MCA stroke onset
demonstrated that IV thrombolysis has < 1% potential to recanalize
occluded vessels if the thrombus length exceeds 8 mm.34
blooming artifact detected on gradient recalled echo (GRE) sequence MRI
scan may be another such characteristic. It has been demonstrated to
closely correlate with the “red clot” composition thought to be more
amenable to chemical thrombolysis than “white clot” composition.35
Although no data support this claim at this time, the presence of the
blooming artifact could predict better outcomes with IA thrombolysis
compared to mechanical endovascular interventions. Indeed, it is
premature to make diagnostic or treatment decisions based on
radiographic correlations of clot composition, as methods for
strengthening these correlations, like using fibrin-specific MRI
contrast agents, are still being innovated.36 MRI and
sonography may have unique roles in this field as their ability to image
the vessel wall and clot allow physicians to determine if the occluding
substance can be lysed or if it requires thrombectomy or stenting for
The goal in acute
stroke management is early recanalization in patients who will benefit
clinically. Stroke centers need to be ready, willing, and able to treat
the appropriate patients in a skilled and compassionate manner. There is
a continuing need for patient education and coordinated systems to
deliver patients to these specialized centers in a timely fashion. Care
should continue to be improved along the dimensions of both earlier
diagnosis and innovative treatment, as well as in the safe and effective
selection of patients for treatment. The radiologist can play a central
role in facilitating the patient care process. We must make it known to
patients, emergency medical technicians, and ED physicians that stroke
can be treated similarly to myocardial infarction, where collaborative
teams improve patient outcomes.37 Radiologists can become an
integral part of the patient care plan and evolve into a crucial part of
the stroke team, both as diagnosticians and as interventionalists. We
can be collaborative in improving time to ER, ER to imaging, and imaging
Applying rigid time windows to decide whether
patients receive systemically administered thrombolytics or endovascular
interventions does not provide sufficiently personalized care.
Multimodal imaging-based criteria, such as perfusion-diffusion mismatch,
DWI lesion volume, blood-brain barrier permeability, and cerebral blood
flow thresholds, promise to make patient selection more individualized
(Tables 2-4). Imaging should continue to evolve and separate out true
penumbra from benign oligemia. However, none of this multimodal imaging
accounts for the physiology of a particular individual’s brain
parenchyma. Some may have extensive previous vascular disease and not be
able to tolerate small additional insults, while other patients have
extensive reserve. Until we are able to appreciate the quality of brain
tissue (ie, molecular markers that predict unfavorable responses to
reperfusion) as well as to use clot composition prospectively to guide
treatment, we will not have truly personalized stroke care.
goal of early intervention in the proper patient remains a challenge; we
need to be active advocates in this emerging field of acute stroke
- Tissue plasminogen activator for acute ischemic stroke. The National
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- Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359:1317-1329.
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- Yoo AJ, Frei D, Tateshima S, et al. The Penumbra Stroke System: A technical review. J Neurointerv Surg. 2011.
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