Ischemic Stro ke

Advances in Diagnosis and Management

Courtney R. Cassella, MD, Andy Jagoda, MD, FACEP*

KEYWORDS
 Acute ischemic stroke  Thrombolysis  Alteplase  Thrombectomy

KEY POINTS
 Tissue plasminogen activator (tPA) (Alteplase) is an treatment approved for treatment of
acute ischemic stroke for patients who meet inclusion criteria and who are treated in
the appropriate setting.
 The risk of symptomatic hemorrhagic conversion in properly selected patients can be less
than 2% with no increase in disability or mortality; conversely, the risk can be greater than
15% in patients with significant comorbidities.
 A decision not to use tPA in the appropriate setting is acceptable, but clinical decision-
making must be well supported in the medical record.
 The earlier the treatment for acute ischemic stroke, the better the outcome.
 Exclusion criteria for tPA have been revised: minor strokes, severe strokes, age, and
seizures must be placed in context of risk/benefit.

INTRODUCTION

The 3 broad categories of stroke are ischemic (87%), hemorrhagic (10%), and sub-
arachnoid hemorrhage (3%).1,2 The specific definition is brain, spinal cord, or retinal
cell death secondary to infarction. Of ischemic strokes, 60% are thrombotic, and
40% are embolic. The brain in ischemic stroke has a core infarct area and ischemic
penumbra. The penumbra represents an area that may be salvaged with prompt
reperfusion. The neurologic deficit can be devastating, and stroke remains the leading
cause of disability and fourth most common cause of death in the United States.2
In the United States, approximately 795,000 people suffer a stroke annually, 77% of
which are new strokes and 23% are recurrent.2 The lifetime risk of stroke from age 55
to 75 years is 20% in women and 15% in men.3 Approximately 10% of patients with an

Disclosure Statement: Dr A. Jagoda is on the Executive Committee of the Brain Attack Coali-
tion; he has indirectly received honorariums from Vindico, a medical education company,
which received an educational grant from Genentech.
Mount Sinai Department of Emergency Medicine, Icahn School of Medicine at Mount Sinai,
One Gustave Levy Place, Box 1620, New York, NY 10128, USA
* Corresponding author.
E-mail address: Andy.Jagoda@mssm.edu

Emerg Med Clin N Am 35 (2017) 911–930

http://dx.doi.org/10.1016/j.emc.2017.07.007 emed.theclinics.com
0733-8627/17/ª 2017 Elsevier Inc. All rights reserved.
912 Cassella & Jagoda

acute ischemic stroke (AIS) die within 1 year, and 20% to 25% of patients remain
severely disabled.4–7
There have been advances in prevention, diagnosis, and therapy over the past
22 years since the National Institute of Neurologic Disorders and Stroke (NINDS) trial
was published demonstrating a higher likelihood of having a favorable clinical
outcome at 3 months when tPA (Alteplase) was administered versus placebo.1 Since
then, several other studies and data base analyses have supported the benefit of tPA
within the appropriate time window,4–7 and its use is recommended by all major
societies, including the American College of Emergency Physicians, the American
Stroke Association (ASA), and the American Academy of Neurology.8–11 This review
provides a summary of guideline recommendations with a primary focus on the
advances in thrombolytic inclusion/exclusion criteria, diagnostic neuroimaging, and
management of large vessel occlusion (LVO).

STROKE ASSESSMENT AND DIFFERENTIAL DIAGNOSIS

The assessment for stroke often starts with prehospital measures by emergency
medical services (EMS). Activation of EMS is recommended by the ASA based on
evidence showing activation improves door-to-needle times, and thus may be related
to improved outcomes (Class I; Level B evidence, see “Applying Classification of
Recommendations and Level of Evidence” at reference 12 for grading scheme11).12,13
As EMS plays a crucial role in stroke timelines, the emergency physician (EP) must be
aware of prehospital history, assessment tools, and interventions.
The prehospital history emphasizes time of symptom onset, history of diabetes,
prior stroke, seizures, hypoglycemia, hypertension, and atrial fibrillation. Additional
history aids in the assessment for tPA eligibility, including medications such as anti-
platelet/anticoagulants, surgeries within the past 3 months, and head or other major
trauma.
The history is performed in conjunction with assessment tools for stroke. In the pre-
hospital setting, the 2 most commonly used tools are the Los Angeles (LAPSS)14 and
Cincinnati Prehospital Stroke Screen (CPSS)15 (Class I; Level B evidence11). Both
screens activate stroke notification if any point is abnormal. The LAPSS includes
asymmetry of facial smile/grimace, grip, and arm strength/drift. The CPSS assesses
for unilateral facial droop, unilateral arm drift, and slurred speech. Given advance-
ments in LVO management, Perez de la Ossa and colleagues16 developed the Rapid
Arterial Occlusion Evaluation (RACE) scale as a prehospital tool to assess stroke
severity and possibly identify LVO with the premise that patients identified as high
risk of LVO are best transferred to a stroke center with endovascular capabilities.
The RACE scale was derived from National Institutes of Health Stroke Scale (NIHSS)
items that highly correlate with LVO. The scale encompasses 5 items rated in score
0 to 2, including facial palsy, arm motor function, leg motor function, head and gaze
deviation, and aphasia or agnosia. In the validation study, a score of 5 showed sensi-
tivity 0.85, specificity of 0.68, positive predictive value of 0.42, and negative predictive
value of 0.94 for LVO.16 Despite the promising data, further study is warranted to
further validate scales for LVO risk stratification.17
Focused prehospital measures include standard ABCs, intravenous (IV) access, car-
diac monitoring, and correction of hypoglycemia. Given that hypoglycemia can be a
stroke mimic, fingerstick glucose should be checked by EMS (Class I; Level B evi-
dence11), and if less than 60 mg/dL, the patient should be given 50 mL of 50% dextrose.
On arrival to the emergency department (ED), the EP should perform the history,
physical examination, and stabilizing measures. As thrombolysis is a time-sensitive
 Ischemic Stroke 913

therapy, these measures should be accomplished as part of a coordinated team

approach, shown in Table 1.12 History should address signs and symptoms of stroke
mimics, discussed in Box 1.
The ED stroke assessment encompasses the standardized NIHSS.18 This scale,
which ranges from 0 to 42, assists in categorizing stroke into “mild” (1–5), “moderate”
(6 and 13), and “severe” (>13). Lower scores are associated with a smaller risk of hem-
orrhagic conversion after tPA and overall better outcomes. “Mild” strokes can still be
associated with significant disability, and the score alone should not be used as the
sole determinate for thrombolytic eligibility. Physical examination may localize the
lesion, assisting radiology interpretation, further explored in Table 2. The physical
examination must also evaluate for signs of head or other body trauma, signs of
seizure, dysrhythmia, or stigmata of coagulopathy.
In addition to initial stabilization ensuring brain oxygenation and perfusion, blood
glucose assessment and reassessment is fundamental. Diagnostic tests should
include an electrocardiogram, imaging, complete blood count, basic metabolic panel,
coagulation panel (prothrombin time, partial thromboplastin time, international
normalized ratio), and troponin (Class I; Level C evidence11). Of these studies, the
only result required before tPA is glucose determination. Therapy should not be
delayed for coagulation or platelet studies unless there is suspected bleeding abnor-
mality or thrombocytopenia, history of anticoagulation use, or anticoagulation use is
uncertain.11 In retrospective reviews, the rate of unsuspected coagulopathy or throm-
bocytopenia in ischemic stroke is very low, comprising 0.4% with unsuspected
coagulopathy19 and 0.3% with unsuspected thrombocytopenia.20
An essential step before tPA is neuroimaging. Door to imaging times include
25 minutes to initiation of imaging and 45 minutes to interpretation. Commonly,
head noncontrast computed tomography (NCCT) is the imaging modality of choice,
however MRI is an option. In the case of suspected LVO, advanced imaging using
IV contrast should be performed. Additional imaging should not delay the administra-
tion of tPA if the patient is eligible (Class I; Level A evidence11).
Use of contrast in both MRI and CT is relatively contraindicated in patients with
impaired renal function. In computed tomography (CT), contrast can cause
contrast-induced nephropathy (CIN), defined as an absolute increase in serum creat-
inine of greater than 0.5 mg/dL or greater than 25% above baseline within 48 to
72 hours after contrast administration. In patients with no known renal disease, the
risk of CIN is approximately 2% with no reported cases needing hemodialysis.21–23
Therefore, in patients with no known renal disease, practitioners should not wait for
serum creatinine measurements before scanning. Interestingly, a study by Davenport
and colleagues24 stratified patients receiving IV contrast by stable estimated glomer-
ular filtration rate (eGFR); contrast was nephrotoxic in patients with eGFR less than

Table 1
Emergency department care timeline

Action Time
Door to physician 10 min
Door to stroke team 15 min
Door to computed tomography (CT) initiation 25 min
Door to CT interpretation 45 min
Door to drug (80% compliance) 60 min
Door to stroke unit admission 3 h
914 Cassella & Jagoda

Box 1
Ischemic stroke mimics

Central nervous system (CNS) abscess

CNS tumor
Drug toxicity
Hypertensive encephalopathy
Hypoglycemia/Hyperglycemia
Migraine with aura (complicated migraine)
Seizure with postictal paresis, aphasia, or neglect
Psychogenic
Wernicke encephalopathy
Head trauma
Multiple sclerosis, degenerative neurologic disorders
Intracranial hemorrhage
Systemic infection
Syncope

30 (CKD stage 4–5) and did not appear to be nephrotoxic in adults with eGFR greater
than 45 (CKD stage 3A and above). In MRI, contrast in those with eGFR less than 30 is
associated with gadolinium-induced nephrogenic systemic fibrosis or dermatosis.

ADVANCES IN INCLUSION AND EXCLUSION CRITERIA

The Food and Drug Administration (FDA) contraindications for tPA were largely based
on the 1995 NINDS trial.1 The derivation of the trial’s inclusion and exclusion criteria
arose from expert opinion, cardiac literature on thrombolysis, and basic science pub-
lications. Controversies over the tPA contraindications led to extensive research
culminating in a February 2016 ASA Scientific Statement revising the inclusion and
exclusion criteria for AIS (note: this is independent of the FDA-approved package
insert inclusion/exclusion criteria).25
The benefits of tPA have been published in trials demonstrating improved rates of
disability after treatment, based on disability scores.4,6,7,26 Despite this, many patients
do not receive tPA despite presenting within the treatment time window due to an
exclusion criterion.27,28 The changes in the 2016 ASA Statement address these bar-
riers. The FDA approved tPA (Alteplase) for treatment within 3 hours from time of
symptom onset, shown in Table 3. The extended time window to 4.5 hours is
endorsed by all major societies involved in stroke care for patients meeting inclusion
criteria after shared decision making on risks and benefits8–11; however, use beyond
3 hours is not FDA approved, see Table 4.
Modifications in exclusion criteria span 2 broad categories of patients: those at risk
of hemorrhage and those with stroke mimics. High risk of hemorrhage includes prior
stroke in the preceding 3 months, prior intracranial hemorrhage (ICH), and postsur-
gical patients. The data are lacking on the specific risks and time relation after these
events. In the case of prior ICH, the risk likely corresponds to the volume of encepha-
lomalacia from the previous ICH, if the stroke is in the same vascular territory, and
how recently the ICH took place.25 Nevertheless, studies have found only a handful
 Ischemic Stroke 915

Table 2
Stroke syndromes

Distribution Deficits
Anterior cerebral artery (ACA) Paratonic rigidity, abulia: lack of initiative
Contralateral motor (more commonly lower
extremity)
Contralateral sensory (more commonly lower
extremity)
Gait apraxia
Middle cerebral artery (MCA) Homonymous hemianopia
Neglect (nondominant)
Aphasia: Wernicke, Broca
Contralateral motor (more commonly face and upper
extremity, more than lower extremity but can have
frank hemiplegia)
Contralateral sensory
Penetrating; also known as Dysarthria
lacunar Internal capsule: contralateral pure motor
Thalamus: contralateral pure sensory
Cerebellar: ipsilateral ataxia
Posterior cerebral artery (PCA) Occipital cortex (visual): homonymous hemianopia,
macula sparing, visual perseverations
Cranial nerve (CN) III palsy: paresis of vertical eye
movements
Alexia without agraphia
Cerebral peduncle, midbrain: motor, sensory,
choreoathetosis
Thalamus: spontaneous pain
Vertebrobasilar Dizziness, nausea, vomiting, coma
CN palsies, diplopia
Dysarthria, dysphagia, hiccups
Motor deficit crossed sensory deficit: ipsilateral face
and contralateral body involvement
Limb/gait ataxia
Anterior spinal artery Caudal medulla (CN XII): tongue deviates ipsilateral
Contralateral motor deficit
Contralateral proprioception
Posterior inferior cerebellar Vertigo, vomiting, nystagmus
artery (PICA) Ipsilateral Horner syndrome: ptosis, anhidrosis, miosis
CN IX-X deficit: dysphagia, hoarseness, decreased gag
Contralateral limb and ipsilateral face pain,
temperature
Ipsilateral ataxia, dysmetria
Anterior inferior cerebellar Vertigo, vomiting, nystagmus
artery (AICA) CN VII deficit: decreased lacrimation
CN V: decreased corneal reflex, ipsilateral Horner
syndrome
Facial motor, pain, and temperature

of patients who were given tPA with prior ICH.29,30 For prior stroke 3 months,
studies by Karlinski and colleagues31,32 suggest no increase in symptomatic ICH
(sICH) if readministering tPA. Based on these limited data, tPA is still considered
potentially harmful in the cases of prior stroke and prior ICH (Class III; Level B
evidence).25 However, for prior stroke 3 months, the potential risks and benefits
916 Cassella & Jagoda

Table 3
Noncontrast CT findings in acute stroke

Imaging Finding Description

Dense middle cerebral artery Increased density in a major cerebral artery
(MCA)/MCA dot sign Dot: distal MCA branches in the sylvian fissure
Hypodensity of lentiform nucleus Loss of definition between the putamen and globus
pallidus
Insular ribbon sign Loss of definition of the gray-white interface in the
lateral margins of the insula
Loss of gray/white differentiation Loss of distinction between gray and white matter,
especially between the basal ganglia and internal
capsule or insular or frontoparietal cortex and
underlying white matter
Hypodensity Cytotoxic edema and increased water content,
commonly quantified by increased Hounsfield Units

of tPA should be discussed during the decision-making process (Class I; Level C

evidence)25 (Tables 5–7).
Patients with recent major surgery have a risk of surgical site hemorrhage after tPA.
There is only Level C evidence, limited population or expert consensus, available.
Reviews of off-label use of tPA include small numbers of 3-month postsurgical
patients with scattered incidence of systemic hemorrhage.33,34 Thus, for carefully
selected patients at fewer than 14 days after surgery, the risk of surgical site hemor-
rhage should be weighed against the benefit of treatment (Class IIb; Level C
evidence).25
Originally, seizure at the beginning of stroke onset, hypoglycemia, and hyperglyce-
mia were exclusion criteria, as these can have presentations that mimic stroke. It is
estimated that 6% to 30% of patients presenting as acute stroke are found to have
a stroke mimic, and 2% to 4% of patients treated as an acute stroke with tPA have
a mimic.35–38 Fortunately these patients do well with extremely low likelihood of hem-
orrhage; that is, less than 0.5% (95% confidence interval [CI] 0%–2%).36–38
Severe, mild, and rapidly resolving stroke symptoms in the past were listed as
exclusion criteria for treatment. Severe strokes, that is, NIHSS greater than 24, were
historically contraindicated, as these patients often have poor outcomes and an
increased risk of sICH.39 However, studies have demonstrated that patients with se-
vere strokes have a better functional outcome when treated with tPA.26,40,41 Addition-
ally, the relative increase in sICH between tPA versus placebo is the same irrespective
of stroke severity.41,42 On the other end of the spectrum, mild stroke is no longer
considered an absolute contraindication for treatment in that it can still lead to signif-
icant disability, and the risk of sICH is considerably less than the 6.4% composite risk
reported for all stroke types combined. For example, a patient with an NIHSS of 2 sec-
ondary to a speech deficit can be significantly impaired and consequently disabled un-
less treated. In one study, 28.3% of patients with mild stroke who did not receive tPA
were not discharged home and 28.5% were not able to ambulate.43 Hence, tPA is rec-
ommended based on clinical judgment of disability and not exclusively on the NIHSS.
Neurology consultation and discussion of the specific deficits is recommended.
Rapidly improving stoke symptoms were also once used to exclude patients with
acute stroke from treatment. However, it has been recognized that strokes can
have a stuttering presentation, and there can be periods of improvement followed
by rapid deterioration.44,45 Even with rapid improvement, especially in LVO, patients
 Ischemic Stroke 917

Table 4
American Heart Association (AHA) Guidelines Exclusion Criteria less than 3 hours

AHA 2013 Update AHA 2016

Significant head trauma in previous 3 mo
Prior stroke in previous 3 mo Removed: The potential for increased risk
of symptomatic intracranial
hemorrhage is not well established
(Class IIB; Level B) however should be
weighted against anticipated benefits
(Class I; Level C)
Symptoms suggest subarachnoid Subarachnoid hemorrhage
hemorrhage
Arterial puncture at noncompressible site in previous 7 d
History of previous intracranial Removed: Warning for recent intracranial
hemorrhage hemorrhage
History of intracranial neoplasm Modified: Contraindicated in intra-axial
intracranial neoplasm (Class III; Level C).
Probably recommended in extra-axial
intracranial neoplasm (Class IIA;
Level C)
History of arteriovenous malformation Modified: Increased risk of intracranial
or aneurysm hemorrhage; however, may be
considered in severe neurologic deficits
and high likelihood of morbidity and
mortality (Class IIB; Level C)
Intracranial or intraspinal surgery within 3 mo
Elevated blood pressure Current severe uncontrolled
(systolic >185 mm Hg or hypertension
diastolic >110 mm Hg) No specific values
Active internal bleeding
Infective endocarditis
Acute bleeding diathesis
Platelet count <100,000 mm3
Heparin within 48 h with elevated activated partial thromboplastin time
Use of direct thrombin inhibitors or direct factor Xa inhibitors with elevated laboratory tests
Current use of anticoagulation with international normalized ratio >1.7 or prothrombin
time >15 s

Data from Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of patients
with acute ischemic stroke: a guideline for healthcare professionals from the American Heart
Association/American Stroke Association. Stroke 2013;44(3):870–947; and Demaerschalk BM, Klein-
dorfer DO, Adeoye OM, et al. Scientific rationale for the inclusion and exclusion criteria for intra-
venous alteplase in acute ischemic stroke: a statement for healthcare professionals from the
American Heart Association/American Stroke Association. Stroke 2016;47(2):581–641.

may still ultimately deteriorate and have profound disability.46 Consequently, rapidly
improving deficits are no longer an absolute exclusion; instead, the total clinical pre-
sentation must be placed in the context of risk for delayed progression.

ADVANCES IN DIAGNOSTIC IMAGING

In AIS, neuroimaging is essential, as it may identify the etiology of stroke, location

of the lesion, potential stroke mimics, or contraindications to thrombolysis. The
918 Cassella & Jagoda

Table 5
American Heart Association (AHA) guidelines exclusion criteria less than 3 h

Relative Exclusion
AHA 2013 Update AHA 2016
Blood glucose concentration <50 mg/dL Removed: It is reasonable to consider tissue
plasminogen activator (tPA) after
glycemic management (dextrose) and
neurologic reexamination within 15 min
Computed tomography demonstrates Removed: There is insufficient evidence to
multilobar infarction (hypodensity > identify a threshold of hypoattenuation.
one-third cerebral hemisphere) However, tPA in extensive regions of
AHA 2013 Class III, Level A clear hypoattenuation is not
recommended (Class III; Level A)
Minor or rapidly improving stroke Removed
symptoms
Pregnancy
Seizure at onset with postictal residual Removed (Class IIa; Level C)
neurologic deficits
Major surgery or serious trauma within Removed: tPA may be considered with risks
previous 14 d of bleeding weighted against severity
and potential disability (Class IIb; Level C)
Gastrointestinal or urinary tract Gastrointestinal or urinary tract
hemorrhage within previous 21 d hemorrhage
Acute myocardial infarction (MI) within Modified: Reasonable if MI was non–ST-
previous 3 mo elevation MI (STEMI) (Class IIa: Level C) or
STEMI involving the right or inferior
myocardium (Class IIa; Level C) or STEMI
involving left anterior myocardium (Class
IIb; Level C)

Data from Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of patients
with acute ischemic stroke: a guideline for healthcare professionals from the American Heart As-
sociation/American Stroke Association. Stroke 2013;44(3):870–947; and Demaerschalk BM, Klein-
dorfer DO, Adeoye OM, et al. Scientific rationale for the inclusion and exclusion criteria for
intravenous alteplase in acute ischemic stroke: a statement for healthcare professionals from the
American Heart Association/American Stroke Association. Stroke 2016;47(2):581–641.

2013 ASA Guidelines have a Class I recommendation for obtaining head NCCT
imaging in suspected stroke.11 NCCT offers both logistical and practical advan-
tages as the first neuroimaging modality. Logistically, NCCT has wide availability,
rapidity of imaging, and overall fewer contraindications. CT is a fast modality,
with a total scan time generally less than 5 minutes, compared with MRI protocols
of 10 to 15 minutes not including additional time delays secondary to scanner avail-
ability, screening for imaging safety, and ensuring scanner-compatible equipment.
Other issues with MRI use include patient claustrophobia and movement artifact.
Furthermore, MRI is contraindicated in patients with noncompatible pacemakers,
metal implants, or foreign bodies. Practically, NCCT evaluates for stroke mimics
such as intracranial mass lesions and contraindications to fibrinolysis, such as
intracranial hemorrhage.
Early NCCT findings that indicate AIS include dense middle cerebral artery
(MCA)47/MCA dot48 sign, loss of gray and white matter differentiation,49 insular ribbon
sign,50 hypodensity of lentiform nucleus,51 and tissue hypodensity.52 These are
discussed in Table 3 and Fig. 1.
 Ischemic Stroke 919

Table 6
American Heart Association (AHA) guidelines inclusion and exclusion criteria less than 4.5 h

Inclusion
Diagnosis of ischemic stroke causing measurable neurological deficit
Onset of symptoms within 3.0–4.5 h

Relative Exclusion
AHA 2013 Updated AHA 2016
Aged >80 y Removed: In >80 y tissue plasminogen
activator (tPA) is safe and can be as
effective as in younger patients (Class IIa,
Level B)
Severe stroke (National Institutes of Health
Stroke Scale >25)
Taking an oral anticoagulant regardless of Modified: Taking oral anticoagulation with
international normalized ratio (INR) an INR <1.7 tPA appears safe and may be
beneficial (Class IIa; Level B)
History of both diabetes and prior ischemic Removed: tPA may be as effective as in the
stroke 0–3-h window (Class IIb: Level B)

Data from Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of patients
with acute ischemic stroke: a guideline for healthcare professionals from the American Heart
Association/American Stroke Association. Stroke 2013;44(3):870–947; and Demaerschalk BM, Klein-
dorfer DO, Adeoye OM, et al. Scientific rationale for the inclusion and exclusion criteria for intra-
venous alteplase in acute ischemic stroke: a statement for healthcare professionals from the
American Heart Association/American Stroke Association. Stroke 2016;47(2):581–641.

Numerous studies have been performed to correlate prognosis or probability of

stroke with these findings. Of these studies, tissue hypodensity may increase the
risk of hemorrhage from fibrinolysis. In particular, tissue hypodensity seen in greater
than 33% of the MCA territory correlates with worse outcomes, including increased
risk of hemorrhage, and consequently this finding provides a contraindication for
thrombolysis.52,53
As there is variability in approximation of the one-third MCA rule, the Alberta Stroke
Program Early CT Score (ASPECTS) was developed to better quantify early ischemic
changes.54 ASPECTS is determined based on 2 standardized NCCT axial cuts, one at
the level of the thalamus and basal ganglion and one at the superior margin of the
ganglionic structures; at these 2 levels there are 10 distinct regions. The score is
calculated by deducting 1 point for each region that demonstrates early ischemic
change such as focal swelling or hypoattenuation. Several studies have used
ASPECTS in conjunction with other imaging modalities such as CT angiography
(CTA), CT perfusion (CTP), or MRI to predict outcomes of stroke parameters.55–57
ASPECT scores less than 6 are a relative contraindication to thrombectomy,
discussed as follows.58,59
Following NCCT, additional imaging is often obtained to evaluate for large-vessel
disease or ischemic penumbra. A noninvasive intracranial vascular study is
required if contemplating endovascular therapy (Class I; Level A evidence).59–64
Head CTA is a common adjunct, as the patient is already in the CT suite. CTA
has benefits over MRI or Transcranial Doppler (TCD), in that it is widely available,
has rapid image acquisition, and includes images of the aorta and neck vessels
for endovascular planning.65 In addition, angiography of the neck may evaluate
for carotid dissection and for carotid vessel atherosclerotic disease, a stroke risk
factor. MRI may be used to evaluate vasculature; however, CT has far fewer
920 Cassella & Jagoda

Table 7
Endovascular therapy trials

Trial (n) Inclusion Outcome (Intervention vs Control)

MR CLEAN (500) <6 h mR, 0–2 @ 90 d: 32.6% vs 19.1%
Distal ICA NIHSS @ 24 h: 13 vs 16
MCA (M1/M2) NIHSS @ 5–7 d: 8 vs 14
ACA (A1/A2) Reperfusion, mTICI 2b/3: 58.7%
NIHSS 2 No significant difference in sICH or
death
New ischemic CVA in new area:
5.6% vs 0.4%
EXTEND-IA (70) <6 h mR, 0–2 @ 90 d: 71% vs 40%
Distal ICA NIHSS @ 24 h:
MCA (M1/M2) NIHSS @ 5–7 d:
Eligible for IV tPA at 4.5 h Reperfusion, mTICI 2b/3: 86%
CT perfusion No significant difference in sICH or
mR <2 death
Ischemic core <70 mL
ESCAPE (316) <12 ha mR, 0–2 @ 90 d: 53% vs 29.3%
Distal ICA NIHSS @ 24 h: 6 vs 13
MCA (M1/M2) NIHSS @ 5–7 d: 2 vs 8
Reperfusion, mTICI 2b/3: 72.4%
No significant difference in sICH
Mortality 10.4 vs 19% (P 5 .04)
SWIFT PRIME <6 h mR, 0–2 @ 90 d: 60% vs 35%
(196) Distal ICA Change in NIHSS @ 27 h:
M1 MCA 8.5  7.1 vs 3.9  6.2
Reperfusion, mTICI 2b/3: 88%
No significant difference in sICH or
death
REVASCAT <8 hb mR, 0–2 @ 90 d: 43.7% vs 28.2%
(206) M1 MCA NIHSS @ 24 h: 13 vs 16
 Distal ICA NIHSS @ 5–7 d: 8 vs 14
Received IV tPA <4.5 h, no Reperfusion, mTICI 2b/3: 65.7%
revascularization after 30 min No significant difference in sICH or
or contraindications to IV tPA death
mR <2, NIHSS 6
ASPECTS 7

Abbreviations: ACA, anterior cerebral artery; CVA, cerebrovascular accident; ICA, internal carotid
artery; IV, intravenous; MCA, middle cerebral artery; mR, modified Rankin; mTICI, modified treat-
ment in cerebral ischemia; NIHSS, National Institutes of Health Stroke Scale; sICH, symptomatic
intracranial hemorrhage; tPA, tissue plasminogen activator
a
Only 15.5% of patients randomized greater than 6 h, not powered to assess therapy separately
for this time range.
b
Only 12.6% of patients randomized greater than 6 h.

contraindications. In addition to the contraindications listed previously in NCCT,

contraindications for contrast CT or MRI include allergy to contrast or stage 4 or
5 chronic kidney disease (eGFR <30).62
CTP protocols were developed to identify the ischemic penumbra and hence the
ideal target for reperfusion. CTP requires postprocessing technology to yield mean
transit time (MTT), cerebral blood volume (CBV), and cerebral blood flow (CBF)
maps. In an oversimplification, CBV indicates area of core infarct, whereas MTT and
CBF delineate the potentially salvable penumbra. An example is shown in Fig. 2.
 Ischemic Stroke 921

Fig. 1. Early signs (<6 hours) of cerebral infarction on noncontrast head CT. High density in
the proximal MCA is thought to represent an acute thrombus lodged in the middle cerebral
artery, and is referred to as the “hyperdense MCA sign” (arrow in A). The presence of edema
in the distribution of the lenticulostriate arteries produces loss of the normal striated
appearance of the insular cortex or “insular ribbon sign” (arrow in B) and local hypoatten-
uation in the basal ganglia, or “obscuration of the lentiform nuclei” (arrow in C). Loss of
gray-white matter differentiation and sulcal effacement (region between the 2 arrows
in D) indicate diffuse cerebral swelling and, of the described signs, carry the poorest clinical
prognosis. (From Kunst MM, Schaefer PW. Ischemic stroke. Radiol Clin North Am
2011;49(1):126.)

CTP in conjunction with CTA can give valuable information on collateral blood flow and
the ischemic penumbra to better identify candidates for reperfusion, although this is
still in need of further research.66,67 A study by Turk and colleagues68 demonstrated
that patients selected for endovascular therapy based on CTP instead of time cutoffs
had similar rates of good functional outcome and sICH. The ASA suggests that CTP or
MRI perfusion may have a role in reperfusion therapy beyond the window for IV fibri-
nolysis (Class IIB; Level B evidence).11 Two thrombectomy trials, EXTEND-IA and
SWIFT PRIME, both included CTP exclusion criteria, discussed later in this article.61,64
Criticisms of CTP predominantly arise from limitations in brain coverage, variations in
922 Cassella & Jagoda

Fig. 2. CT perfusion imaging of acute left MCA infarct. Example of radiological findings in a
patient with a right hemisphere stroke who underwent successful recanalization: baseline
perfusion CT: (A) CBF, (B) CBV. (C) CTA shows right MCA occlusion; (D) 24-hour NCCT. The
mismatch between the area of reduced CBV and the area of reduced CBF represents the
penumbral zone. The infarct at 24 hours correlates with the area of reduced CBV. (From
Kawiorski MM, Vicente A, Lourido D, et al. Good Clinical and Radiological Correlation
from Standard Perfusion Computed Tomography Accurately Identifies Salvageable Tissue
in Ischemic Stroke. J Stroke Cerebrovasc Dis 2016;25(5):1062–9.)

postprocessing methods, and delays in interpretation.69 Newer-generation whole-

brain CT scanners, standardization in software, and increasing experience will poten-
tially address these concerns.
Although CT has many strengths, MRI allows better visualization of brain paren-
chyma if using diffuse weighted sequences. MRI diffusion has the benefit of better
visualization of the posterior fossa and of characterizing small strokes that are often
missed on CT, see Fig. 3.70 With the increased resolution, MRI identifies cerebral
microbleeds (CMBs). The cause of CMBs is unclear and may represent reperfusion
injury or disrupted cerebral autoregulation.25 Regardless, the Bleeding Risk Analysis
in Stroke Imaging Before Thrombolysis (BRASIL) study found no significant differ-
ence in sICH in patients with CMBs treated with tPA versus those without
CMBs.71,72
 Ischemic Stroke 923

Fig. 3. (A) Subtle hypodensity in the right putamen and insula. Concurrent MRI diffusion-
weighted (B) and apparent diffusion coefficient (C) images delineate a larger region of
ischemic injury involving the right basal ganglia, insula, and frontal operculum. (Data
from Yoo AJ, González RG. Clinical applications of diffusion MR imaging for acute ischemic
stroke. Neuroimaging Clin N Am 2011;21(1):51–69, vii.)

ADVANCES IN MANAGEMENT OF LARGE VESSEL OCCLUSION

LVO is associated with high rates of morbidity and mortality secondary to the lesion
itself and complications such as hemorrhage and edema. Further supporting the
need for decisive management of LVO, only 25% to 30% of patients with LVO who
receive tPA will recanalize.73,74 Early studies using angioplasty, stenting, or arterial
thrombolytics were promising but showed limited success.75–81 However, 2015 was
a “break-through” year for the use of new-generation stent retriever devices.
Five seminal stent retriever trials changed the landscape of LVO treatment: MR
CLEAN,60 EXTEND-IA,61 ESCAPE,62 REVASCAT,63 and SWIFT PRIME.64 Study
design and characteristics were similar encompassing multicenter, prospective,
randomized, open clinical trials. Providers should consider the large number of
patients screened in these studies to use these interventions. Most investigated endo-
vascular clot retrieval within a 6-hour window. ESCAPE and REVASCAT extended the
interval to 12 hours and 8 hours, respectively; however, the proportions of patients
after 6 hours was less than 20% and not powered to assess therapy separately for
extended time points. All gave standard dosing intravenous tPA (0.9 mg/kg body-
weight) if eligible. All of these studies had some CT imaging criteria to target LVO,
predominantly M1 MCA or internal carotid artery (ICA) distribution, although some
studies did include M2 MCA and A1/A2 anterior cerebral artery (ACA). Most of these
studies used inclusion criteria of age 18 years, ASPECTS 6, CTP with core infarct
less than 70 mL,34,36 good prestroke functional status, and/or NIHSS score 6. Base-
line characteristics were typically balanced between intervention and control groups,
including a median NIHSS of 17 across all study participants.56–60
The 5 trials demonstrated endovascular (EV) therapy promoted recanalization with
significant improvement in modified Rankin scores (mRS) with no increase in sICH or
mortality, discussed further in Table 6. The number needed to treat for endovascular
thrombectomy to reduce disability at least one level of mRS is 2.6.82 Effect improved in
specific groups including age older than 80 years (OR 3.68, 95% CI 1.95–6.92), more
than 300 minutes after symptom onset (1.76, 1.05–2.97), and those not eligible for tPA
(2.43, 1.30–4.55).82
Given the significant effect of EV therapy, it is recommended that stroke systems
try to improve accessibility to the intervention. This is a challenge that will take
time and money to meet. The stent retriever trials occurred at institutions with
924 Cassella & Jagoda

neuro-interventionalists or systems of care with prompt transfer capabilities. ASA

recommends that patients should be transported rapidly to primary or comprehensive
stroke centers (Class I; Level A evidence), and regional systems of stroke care should
be developed to provide access to centers capable of performing endovascular stroke
treatment (Class I; Level A evidence).59

SHARED DECISION MAKING AND POTENTIAL COMPLICATIONS FROM TREATMENT

sICH is a major concern related to the use of thrombolytics in AIS. Intracranial hemor-
rhage is classified as either symptomatic or asymptomatic. sICH is defined as new
hemorrhage not seen on prior CT or suspicion of hemorrhage as a cause of neurologic
deterioration. The composite risk of sICH from tPA when all stroke types are combined
is 6.4% (vs 0.6% in placebo).7,42 However, risk must be adjusted for stroke type and
comorbidities; this is particularly important when engaging patients or their surrogates
in the informed consent or shared decision-making (SDM) process. In this discussion,
benefits including improved functional outcome and deficits should be weighed
against risks, particularly sICH. The discussion should include individualized expecta-
tions including but not limited to functional status before stroke and comorbidities. The
Totaled Health Risks in Vascular Events (THRIVE) score was developed as a prediction
score for ischemic stroke outcomes.83–86 The THRIVE score assigns 1 point for age 60
to 79 years, 2 points for 80 years, 2 points for NIHSS score 11 to 20, 4 points for
NIHSS 21, and 1 point each for hypertension, diabetes, and atrial fibrillation. For
each increasing point, the odds ratio of sICH increases 1.21.86 A THRIVE score of
1 is correlated with a 3% incidence of sICH, whereas a THRIVE score of 7 is associ-
ated with a 15% incidence. Consequently, understanding the factors linked to risk for
sICH is an important component of the SDM process.
If opting to proceed with tPA, the EP should monitor for hemorrhage and angioe-
dema. The EP should discontinue the tPA infusion and obtain an emergency CT
scan if there is a change in the patient’s level of consciousness or if there is a new se-
vere headache, change in pupil size and reactivity, new nausea and vomiting, or acute
hypertension. Although poorly studied, treatments have included reversal as well as
consultation for surgical decompression or hematoma evacuation.11 Replacement
of clotting factors or reversal is attempted with cryoprecipitate, fresh frozen plasma,
vitamin K, platelet transfusion, recombinant factor VIIa, and aminocaproic acid.
A study by Yaghi and colleagues87 found patients with hematoma expansion had
severe hypofibrinogenemia, highlighting the role of cryoprecipitate.
Angioedema, defined as swelling of the tongue, lips, or oropharynx, after intrave-
nous tPA is estimated to occur in 1% to 5% of all patients.88–90 This reaction is typi-
cally mild, transient, and contralateral to the ischemic hemisphere.89 After
administration of tPA, patients should be monitored for angioedema. If symptoms
occur, treatment includes IV ranitidine, diphenhydramine, and methylprednisolone.90

SUMMARY

tPA (Alteplase) is FDA approved for the treatment of AIS. Outcomes are related to time
to treatment, thus emphasizing the importance of rapid EMS activation and transport,
and hospital-based stroke teams with protocols that facilitate minimizing “door-to-
needle times.” Prehospital assessment scales may be used to aid in stroke activation
and triage to comprehensive stroke centers. Evaluation and diagnostic studies should
be attained rapidly with the goal of “door-to-needle time” within 60 minutes.
Exclusion criteria for thrombolytic therapy has been revised based on analysis of
outcomes from large data bases; minor stroke, severe stroke, rapidly improving
 Ischemic Stroke 925

stroke, advanced age, seizure, history of stroke, history of intracranial hemorrhage,

and recent surgery are no longer exclusionary, and risk versus benefit must be taken
into consideration. SDM is encouraged when possible. The THRIVE score may help
facilitate discussions on the risk of sICH.
Advances in neuroimaging aid in the diagnosis the treatment decisions in AIS.
In select patients, CTA head and neck should be performed to assess for LVO and
eligibility for endovascular therapy. The ASPECT score and CT perfusion are tools
to evaluate extent of infarct and can be incorporated into treatment selection. Endo-
vascular therapy has dramatically improved outcomes from LVOs, and many of these
patients are no longer condemned to a life with severe disability. The future holds
tremendous promise, and continued advances in our ability to diagnose and treat
patients with acute strokes can be anticipated.

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