CHAPTER 167: Stroke Syndromes 1123

TABLE 167-6 National Institutes of Health Stroke Scale (NIHSS)

Instructions Scale Definition
1a. Level of consciousness (LOC) *
0 = Alert; keenly responsive.
The investigator must choose a response if a full evaluation is prevented by such obstacles as an 1 = Not alert, but arousable by minor stimulation to obey, answer, or respond.
endotracheal tube, language barrier, or orotracheal trauma/bandages. A 3 is scored only if the 2 = Not alert; requires repeated stimulation to attend, or is obtunded
patient makes no movement (other than reflexive posturing) in response to noxious stimulation. and requires strong or painful stimulation to make movements (not
stereotyped).
3 = Responds only with reflex motor or autonomic effects or is totally unre-
sponsive, flaccid, and areflexic.
1b. LOC questions 0 = Answers both questions correctly.
The patient is asked the month and his or her age. The answer must be correct—there is no 1 = Answers one question correctly.
partial credit for being close. Aphasic and stuporous patients who do not comprehend the 2 = Answers neither question correctly.
questions are given a score of 2. Patients unable to speak because of endotracheal intubation,
orotracheal trauma, severe dysarthria from any cause, language barrier, or any other problem not
secondary to aphasia are given a score of 1. It is important that only the initial answer be graded
and that the examiner not “help” the patient with verbal or nonverbal cues.
1c. LOC commands 0 = Performs both tasks correctly.
The patient is asked to open and close the eyes and then to grip and release the nonparetic hand. 1 = Performs one task correctly.
Substitute another one-step command if the hands cannot be used. Credit is given if an unequivocal 2 = Performs neither task correctly.
attempt is made but not completed due to weakness. If the patient does not respond to command,
the task should be demonstrated to him or her (pantomime) and the result scored (i.e., follows no,
one, or two commands). Patients with trauma, amputation, or other physical impediments
should be given suitable one-step commands. Only the first attempt is scored.
2. Best gaze 0 = Normal.
Only horizontal eye movements are tested. Voluntary or reflexive (oculocephalic) eye movements 1 = Partial gaze palsy; gaze is abnormal in one or both eyes, but forced
are scored, but caloric testing is not done. If the patient has a conjugate deviation of the eyes deviation or total gaze paresis is not present.
that can be overcome by voluntary or reflexive activity, the score is 1. If a patient has an isolated 2 = Forced deviation, or total gaze paresis not overcome by the oculoce-
peripheral nerve paresis (cranial nerve III, IV, or VI), the score is 1. Gaze is testable in all aphasic phalic maneuver.
patients. Patients with ocular trauma, bandages, preexisting blindness, or other disorder of visual
acuity or fields should be tested with reflexive movements, and a choice made by the investigator.
Establishing eye contact and then moving about the patient from side to side will occasionally clarify
the presence of a partial gaze palsy.
3. Visual 0 = No vision loss.
Visual fields (upper and lower quadrants) are tested by confrontation, using finger counting or 1 = Partial hemianopia.
visual threat, as appropriate. Patients may be encouraged, but if they look at the side of the 2 = Complete hemianopia.
moving fingers appropriately, this can be scored as normal. If there is unilateral blindness or 3 = Bilateral hemianopia (blind including cortical blindness).
enucleation, visual fields in the remaining eye are scored. Score 1 only if a clear-cut asymmetry,
including quadrantanopia, is found. If the patient is blind from any cause, score 3. Double
simultaneous stimulation is performed at this point. If there is extinction, patient receives a
score of 1, and the results are used to respond to item 11.
4. Facial palsy* 0 = Normal symmetric movements.
Ask—or use pantomime to encourage—the patient to show teeth or raise eyebrows and 1 = Minor paralysis (flattened nasolabial fold, asymmetry on smiling).
close eyes. Score symmetry of grimace in response to noxious stimuli in the poorly responsive 2 = Partial paralysis (total or near-total paralysis of lower face).
or noncomprehending patient. If facial trauma/bandages, orotracheal tube, tape, or other physical 3 = Complete paralysis of one or both sides (absence of facial movement in
barriers obscure the face, these should be removed to the extent possible. the upper and lower face).
5. Motor arm 0 = No drift; limb holds 90 (or 45) degrees for full 10 s.
The limb is placed in the appropriate position: extend the arms (palms down) 90 degrees (if sitting) 1 = Drift; limb holds 90 (or 45) degrees, but drifts down before full 10 s; does
or 45 degrees (if supine). Drift is scored if the arm falls before 10 s. (Count out loud and use fingers not hit bed or other support.
to show the patient the count.) The aphasic patient is encouraged using urgency in the voice and 2 = Some effort against gravity; limb cannot get to or maintain (if cued)
pantomime, but not noxious stimulation. Each limb is tested in turn, beginning with the nonparetic 90 (or 45) degrees, drifts down to bed, but has some effort against gravity.
arm. Only in the case of amputation or joint fusion at the shoulder, the examiner should record the 3 = No effort against gravity; limb falls.
score as untestable (UN) and clearly write the explanation for this choice.
4 = No movement.
5a. Left arm
5b. Right arm
6. Motor leg 0 = No drift; leg holds 30-degree position for full 5 s.
The limb is placed in the appropriate position: hold the leg at 30 degrees (the patient is always tested 1 = Drift; leg falls by the end of the 5-s period but does not hit bed.
supine). Drift is scored if the leg falls before 5 s. (Count out loud and use fingers to show the patient 2 = Some effort against gravity; leg falls to bed by 5 s, but has some effort
the count.) The aphasic patient is encouraged using urgency in the voice and pantomime, but not against gravity.
noxious stimulation. Each limb is tested in turn, beginning with the nonparetic leg. Only in the case of 3 = No effort against gravity; leg falls to bed immediately.
amputation or joint fusion at the hip, the examiner should record the score as untestable (UN) and
clearly write the explanation for this choice. 4 = No movement.
6a. Left leg
6b. Right leg
(Continued)
1124 SECTION 14: Neurology

TABLE 167-6 National Institutes of Health Stroke Scale (NIHSS) (Continued)

Instructions
7. Limb ataxia *
This item is aimed at finding evidence of a unilateral cerebellar lesion. Test with the patient’s
eyes open. In case of visual defect, ensure that testing is done in the intact visual field. The
finger-nose-finger and heel-shin tests are performed on both sides, and ataxia is scored only if
present out of proportion to weakness. Ataxia is absent in the patient who cannot understand or is
paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as
untestable (UN) and clearly write the explanation for this choice. In case of blindness, test by
having the patient touch the nose from an extended arm position.
8. Sensory†
Sensation or grimace to pinprick when tested, or withdrawal from a noxious stimulus in the
obtunded or aphasic patient. Only sensory loss attributed to stroke is scored as abnormal, and the
examiner should test as many body areas (arms [not hands], legs, trunk, face) as needed to check
accurately for hemisensory loss. A score of 2, “severe or total sensory loss,” should be given only
when a severe or total loss of sensation can be clearly demonstrated. Stuporous and aphasic
patients will therefore probably score 1 or 0. The patient with brainstem stroke who has bilateral
loss of sensation is scored 2. If the patient does not respond and is quadriplegic, score 2. Patients
in a coma (item 1a score = 3) are automatically given a 2 on this item.
9. Best language
A great deal of information about comprehension is obtained during the preceding sections of
the examination. For this scale item, the patient is asked to describe what is happening in the test
picture, to name the items on the test naming sheet, and to read from the test list of sentences.
Comprehension is judged from responses here as well as responses to all of the commands in the
preceding general neurologic examination. If vision loss interferes with the tests, ask the patient to
identify objects placed in the hand, repeat, and produce speech. The intubated patient should be
asked to write. The patient in a coma (item 1a score = 3) automatically scores 3 on this item.
The examiner must choose a score for the patient with stupor or limited cooperation, but a score
of 3 should be used only if the patient is mute and follows no one-step commands.
10. Dysarthria*
If the patient is thought to be normal, an adequate sample of speech must be obtained by asking
the patient to read or repeat words from the test list. If the patient has severe aphasia, the clarity of
articulation of spontaneous speech can be rated. Only if the patient is intubated or has other physical
barriers to producing speech, the examiner should record the score as untestable (UN) and clearly
write an explanation for this choice. Do not tell the patient why he or she is being tested.
11. Extinction and inattention
Sufficient information to identify neglect may be obtained during the prior testing. If the patient
has a severe vision loss preventing visual double simultaneous stimulation and the responses to
cutaneous stimuli are normal, the score is 0. If the patient has aphasia but does appear to attend to
both sides, the score is 0. The presence of visual spatial neglect or anosognosia may also be taken
as evidence of abnormality. Because the abnormality is scored only if present, the item is never
scored as untestable.
∗
Items not included in the modified NIHSS.43
†
Scale for item 8 is compressed to two elements (0 = normal; 1 = abnormal) for modified NIHSS.43
Source: National Institute of Neurological Disorders and Stroke (NINDS) website (https://www.ninds.nih.gov/sites/default/files/NIH_Stroke_Scale.pdf). Accessed September 11, 2018.
Scale Definition
0 = Absent.
1 = Present in one limb.
2 = Present in two limbs.
0 = Normal; no sensory loss.
1 = Mild-to-moderate sensory loss; patient feels pinprick is less sharp or is
dull on affected side, or there is loss of superficial pain with pinprick,
but patient is aware of being touched.
2 = Severe to total sensory loss; patient is not aware of being touched on
face, arm, and leg.∗
0 = No aphasia; normal.
1 = Mild-to-moderate aphasia; some obvious loss of fluency or facility of
comprehension, without significant limitation on ideas expressed or
form of expression. However, reduction of speech and/or comprehension
makes conversation about provided materials difficult or impossible.
For example, in conversation about provided materials, examiner can
identify picture or naming card content from patient’s response.
2 = Severe aphasia; all communication is through fragmentary expression;
great need for inference, questioning, and guessing by listener. Range
of information that can be exchanged is limited; listener carries burden
of communication. Examiner cannot identify materials provided from
patient’s response.
3 = Mute, global aphasia; no usable speech or auditory comprehension.
0 = Normal.
1 = Mild-to-moderate dysarthria; patient slurs at least some words and, at
worst, can be understood with some difficulty.
2 = Severe dysarthria; patient’s speech is so slurred as to be unintelligible
in the absence of or out of proportion to any dysphasia, or is mute/
anarthric.
0 = No abnormality.
1 = Visual, tactile, auditory, spatial, or personal inattention or extinction to
bilateral simultaneous stimulation in one of the sensory modalities.
2 = Profound hemi-inattention or extinction in more than one modality;
patient does not recognize own hand or orients to only one side of
space.

or three-dimensional figures) may occur. A homonymous hemianopsia
and gaze preference toward the side of the infarct may also be seen,
regardless of the side of the infarction.
POSTERIOR CEREBRAL ARTERY INFARCTION
(DISTAL POSTERIOR CIRCULATION)
The classic symptoms and signs of posterior circulation strokes include
ataxia, nystagmus, altered mental status, and vertigo, but presentation
can sometimes be rather subtle.47 Crossed neurologic deficits (e.g.,
ipsilateral cranial nerve deficits with contralateral motor weakness) may
indicate a brainstem lesion. According to an analysis of a large stroke
registry,48 symptoms of posterior cerebral artery involvement include
unilateral limb weakness, dizziness, blurry vision, headache, and dys-
arthria. Common presenting signs include visual field loss, unilateral
limb weakness, gait ataxia, unilateral limb ataxia, cranial nerve VII signs,
lethargy, and sensory deficits.48 Visual field loss, classically described as
contralateral homonymous hemianopsia and unilateral cortical blind-
ness, is thought to be specific for distal posterior circulation stroke
because the visual centers of the brain are supplied by the posterior cere-
bral artery. Light-touch and pinprick sensation deficits, loss of ability to
read (alexia) without agraphia, inability to name colors, recent memory
loss, unilateral third nerve palsy, and hemiballismus have also been
reported. Motor dysfunction, although common, is typically minimal,
which can keep some patients from realizing they have had a stroke.
BASILAR ARTERY OCCLUSION
(MIDDLE POSTERIOR CIRCULATION)
Occlusion of the basilar artery most commonly presents with symp-
toms of unilateral limb weakness, dizziness, dysarthria, diplopia, and
headache.48 The most common presenting signs are unilateral limb

weakness, cranial nerve VII signs, dysarthria, Babinski sign, and oculo-
motor signs.48 Dysphagia, nausea or vomiting, dizziness, and Horner’s
syndrome are positively correlated with basilar artery occlusion.48 Basilar
artery occlusion can also rarely cause locked-in syndrome, which occurs
with bilateral pyramidal tract lesions in the ventral pons and is character-
ized by complete muscle paralysis except for upward gaze and blinking.
Basilar artery occlusions have a high risk of death and poor outcomes.49,50
VERTEBROBASILAR INFARCTION
(PROXIMAL POSTERIOR CIRCULATION)
Patients with vertebrobasilar infarction most commonly present with
symptoms of dizziness, nausea or vomiting, headache, dysphagia,
unilateral limb weakness, and unilateral cranial nerve V symptoms.48
Common presenting signs include unilateral limb ataxia, nystagmus,
gait ataxia, cranial nerve V signs, limb sensory deficit, and Horner’s
syndrome.48 For further discussion of vertigo, see Chapter 170, “Vertigo.”
CEREBELLAR INFARCTION
Patients with cerebellar infarction can present with very nonspecific
symptoms and can present with dizziness (with or without vertigo),
nausea and vomiting, gait instability, headache, limb ataxia, dysarthria,
dysmetria, nystagmus, hearing loss, and intractable hiccups.51 Mental
status may vary from alert to comatose. Because up to 25% of noncon-
trasted head CTs can be normal in cerebellar infarction,52 if the initial
noncontrasted head CT is unremarkable, obtain an emergent diffusion-
weighted MRI when this diagnosis is suspected. A CT angiogram or
magnetic resonance angiogram is useful to characterize any vascular
lesion once the diagnosis is made. The clinical presentation and course
of cerebellar infarction can be frustratingly difficult to predict, but the
clinician must remain vigilant to the possibility of rapid deterioration
secondary to increased brainstem pressure caused by cerebellar edema.
Therefore, extremely close serial examinations (especially looking for
gaze palsy and altered mental status) and prompt neurologic and neuro-
surgical bedside consultations are needed. Obtain early neurosurgical
consultation for patients with cerebellar infarction. Cerebellar edema
can lead to rapid deterioration with herniation, and consultation is
required to determine the need for emergency posterior fossa decom-
pression in these patients. Acute obstructing hydrocephalus or symp-
tomatic mass effect requires rapid treatment of elevated intracranial
pressure with hyperosmolar therapy (mannitol or hypertonic saline) and
emergent surgical decompression.51
LACUNAR INFARCTION
Lacunar infarcts are pure motor or sensory deficits caused by infarction
of small penetrating arteries and are commonly associated with chronic
hypertension and increasing age. The presentation is variable based on
the location and size of the lesions. The prognosis is generally consid-
ered more favorable than for other stroke syndromes.
CAROTID AND VERTEBRAL ARTERY DISSECTION
Carotid or vertebral artery dissection (collectively referred to as “cervi-
cal artery dissection”) is an uncommon entity (2.6 to 2.9 per 100,000
annually in the general population) that is a major cause of stroke (up
to 20% prevalence) in young adults and the middle-aged.53 A history of
neck trauma in the days to weeks prior to presentation is a prominent
risk factor. The trauma is usually minor54 (e.g., manipulative therapy
of the neck55-57 or sport-related trauma58). Other associated condi-
tions include hypertension,59 large-vessel arteriopathies,60 history of
migraine,61 and heritable connective tissue disease.62
The typical first symptom of patients with carotid or vertebral artery
dissection is unilateral headache (68%), neck pain (39%), or face pain
(10%),63 which can precede other symptoms by hours to days (median,
4 days).64 New-onset headache or neck pain of unclear etiology is such
an important symptom that imaging of the neck vessels is recommended
CHAPTER 167: Stroke Syndromes 1125
by some as part of initial evaluation.65 Symptoms may be transient or
persistent. The median time between an initial presentation of neck
pain and the development of other neurologic symptoms is 14 days,
but if headache is the first symptom, other neurologic symptoms follow
within a median time of 15 hours.64
! CAROTID ARTERY DISSECTION
The headache is most commonly in the frontotemporal region and, due
to its variable quality and severity, may mimic subarachnoid hemor-
rhage (i.e., “thunderclap” headache), temporal arteritis, or preexisting
migraine. A partial Horner’s syndrome (miosis and ptosis) has tradition-
ally been linked to carotid artery dissection, but in reality, it occurs in
only about 25% of patients and is a sign accompanying other disorders
besides stroke.66 Associated cranial nerve palsies have been reported in
12% of carotid artery dissections.67 Carotid dissection can progress to
cause cerebral ischemia or, rarely, retinal infarction.
! VERTEBRAL ARTERY DISSECTION
Vertebral artery dissection commonly presents with dizziness/vertigo
(58%), headache (51% to 65%), and neck pain (46% to 66%).63,68 Both
headache and neck pain can be unilateral or bilateral.63 The headache
is typically occipital, but can rarely present with pain on an entire side
of the head or in the frontal region.69 Other symptoms and signs may
include unilateral facial paresthesia, dizziness, vertigo, nausea/emesis,
diplopia and other visual disturbances, ataxia, limb weakness, numb-
ness, dysarthria, and hearing loss. Cervical radiculopathy (typically a
peripheral motor deficit at the C5 level) is a rare presentation (1%) and
can also involve multiple levels and sensory findings.70 Untreated ver-
tebral artery dissection may result in infarction in regions of the brain
supplied by the posterior circulation.
CT/CT angiography and MRI/magnetic resonance angiography are the
diagnostic modalities of choice for suspected carotid, vertebral, or basi-
lar artery dissection and have similar test performance characteristics.71
The choice of study is usually determined by immediate availability and
patient stability. The sensitivity of color duplex US for the detection of
cervical artery dissection is comparatively low (approximately 92%) and
may miss important vascular lesions.72,73
! TREATMENT OF CAROTID AND VERTEBRAL ARTERY DISSECTION
Cervical artery dissection can cause ischemic stroke via a thromboem-
bolic process, or a decreased blood flow secondary to the vascular lesion
itself, or from a mixed mechanism.74 If a patient with cervical artery
dissection presents with the symptoms of acute ischemic stroke, treat
them similarly to any other stroke patient. Although no large-scale
randomized trials regarding systemic thrombolysis in cervical artery
dissection have yet been published, a meta-analysis of 10 observational
studies (n = 846) concluded that thrombolysis was equally efficacious in
stroke from cervical artery dissection as in stroke from other causes.75
Furthermore, the study determined that thrombolysis in cervical artery
dissection caused no increased incidence of harm when compared to its
use in stroke from other causes.75 Therefore, consider the administra-
tion of IV thrombolytic therapy in all eligible patients with stroke
from cervical artery dissection. The efficacy of endovascular therapy
for cervical artery dissection–related stroke is unclear because the
benefits of endovascular therapy have been shown only for the anterior
circulation (see later section “Endovascular Therapy”), and there is a
paucity of published data to direct care in these patients. For example,
after excluding many studies for low quality, a 2017 meta-analysis study-
ing this issue was able to include only 16 retrospective case reports or
small case series, which had “an overall high risk of bias.”76 Although
the outcome trend in the included data was favorable for endovascular
therapy, the lack of high-quality randomized data makes drawing defini-
tive conclusions difficult. Therefore, if a patient with cervical artery
dissection–related stroke qualifies for consideration of endovascular
therapy, discuss with a stroke neurointerventionalist at a comprehensive
stroke center to help determine the best course of action.
In cervical artery dissection patients who are not candidates for
thrombolysis or endovascular therapy, the two major medical choices
1126 SECTION 14: Neurology
for treatment are anticoagulation or antiplatelet therapy. Historically,
carotid and vertebral artery dissection has been traditionally treated
with IV heparin followed by warfarin (to maintain an INR of 2.0 to
3.0). This treatment has persisted despite the absence of high-quality
randomized controlled trials comparing anticoagulation with other
potentially more effective treatment modalities.77 In 2012 and 2015,
meta-analyses of nonrandomized trials found no difference in patient
outcomes between antiplatelet therapy and anticoagulation.78,79 In 2015,
the Cervical Artery Dissection in Stroke Study was published.80 The
Cervical Artery Dissection in Stroke Study was the first randomized
trial comparing antiplatelet agents (aspirin, dipyridamole, or clopidogrel
alone or in combination [determined by the individual clinician]) to
anticoagulation (heparin [either unfractionated heparin or therapeutic
low-molecular-weight heparin] followed by warfarin) in acute cervical
artery dissection. The Cervical Artery Dissection in Stroke Study
found no difference in patient outcomes between the two treatment
modalities. An important caveat is that based on previous estimates of
recurrent stroke prevalence, the planned study size was small (n =250).
However, during the trial, it was discovered that the prevalence of recur-
rent stroke in both the control and study groups was far lower than
expected and there were no deaths. Based on these data, the authors
determined the study lacked the power to detect a difference between
the two treatment modalities and that the revised sample size to do so
(n = 10,000) made further investigation unfeasible.81 Therefore, pend-
ing the availability of new randomized controlled trial data, administer
either anticoagulant or antiplatelet therapy in the ED if the patient
is not a candidate for IV thrombolysis. Select the specific therapy in
conjunction with appropriate specialist consultation.
! HEMORRHAGIC STROKE SYNDROMES
Spontaneous intracerebral hemorrhage may be clinically indistinguish-
able from ischemic infarction, but the two conditions are distinct clinical
entities in terms of management, with higher levels of morbidity and
mortality for hemorrhage than for ischemic infarction.82,83 Therefore,
perform CT to differentiate between the two. Headache, nausea, and
vomiting often precede the neurologic deficit, and the patient’s condition
may quickly deteriorate (see Chapter 166, “Spontaneous Subarachnoid
and Intracerebral Hemorrhage”).
Cerebellar hemorrhage may be clinically indistinguishable from
cerebellar infarction. The same clinical presentation and management
considerations detailed earlier in this chapter apply (see earlier section
“Cerebellar Infarction”).
Subarachnoid hemorrhage is typically characterized by a severe
occipital or nuchal headache. Patient history includes the recent sudden
onset of a maximal-intensity headache in many cases. Careful history
taking may reveal activities associated with a Valsalva maneuver, such
as defecation, sexual activity, weight lifting, or coughing, at stroke onset.
For further information, see Chapter 166, “Spontaneous Subarachnoid
and Intracerebral Hemorrhage.”
! STROKE DIAGNOSIS
Mimics (Table 167-5)28-30 can often be distinguished from stroke by care-
ful history taking and physical examination, bedside tests, observation,
and appropriate imaging. However, it can be difficult to distinguish
conditions with focal transient symptoms (e.g., seizure) from transient
ischemic attack (TIA).
INITIAL DIAGNOSTIC EVALUATION
The classic mantra, “time is brain,”84 explains the current AHA/ASA
stroke guidelines Class IB recommendation to enact “an organized
protocol for the emergency evaluation of patients with suspected
stroke” in which the primary goal is to achieve a door-to-needle time of
≤60 minutes of ED arrival in ≥50% of acute ischemic stroke patients who
are treated with thrombolytics.19 Based on performance data in hospitals
participating in the “Get with the Guidelines—Stroke” initiative (i.e.,
median door-to-needle time 56 minutes; 30% treated in ≤45 minutes),85
it seems likely that the recommended door-to-needle time goal will
decrease in the future. Creation of a multidisciplinary stroke team is rec-
ommended, along with implementation of quality improvement initia-
tives to “safely increase IV thrombolytic treatment.”19 The culture of the
institution should be aligned to encourage rapid diagnosis and treatment
of stroke. Train triage personnel to suspect stroke and to quickly activate
a stroke critical pathway that includes specific standing orders and pro-
cedures. Implement the critical pathway immediately upon that patient’s
arrival, beginning in the triage area. Notify the emergency physician, the
ED charge nurse, and the CT and laboratory technicians immediately
when acute stroke is suspected. Do not delay the workup because ED
beds are overcrowded or the emergency physician is currently otherwise
engaged. ED core interventions are listed in Table 167-7.19,86-98
Nonessential testing and procedures (including IV starts and blood
draws) should not delay performing brain imaging within 20 minutes of
the patient’s arrival. A summary of time goals is listed in Table 167-8.19
BRAIN IMAGING
Obtain emergency non–contrast-enhanced CT for suspected acute
stroke upon arrival. Most acute ischemic strokes are not visualized by
a noncontrast brain CT in the early hours of a stroke.23 Therefore, the
utility of the first brain CT is primarily to exclude intracranial bleeding,
abscess, tumor, and other stroke mimics, as well as to detect current
contraindications to thrombolytics (e.g., “extensive regions of clear
hypoattenuation”).19
The CT scan should be interpreted by the most expert interpreter
available as soon as it is completed. The identification of subtle hem-
orrhage and early cerebral infarction requires expertise. In hospitals
without on-site experts, telemedicine consultation is an option. Studies
have shown fair to excellent interobserver agreement in CT readings
between telemedicine stroke neurologists and neuroradiologists,99,100
and telemedicine was associated with faster head CT interpretation in a
cohort of 19 rural critical access hospitals.101 In one retrospective study
(n = 1659), even when there were differing CT interpretations between
telemedicine stroke neurologists and overreading neuroradiologists
in patients who received thrombolytics, there was no association with
thrombolysis-related symptomatic intracranial hemorrhage.99
Diffusion-weighted MRI is superior to non–contrast-enhanced CT
or other types of MRI (T1/T2 weighted, fluid-attenuated inversion
recovery) in the detection of acute infarction.102,103 However, CT’s
superior rapid availability, MRI’s patient-specific contraindications
(lack of cooperation, claustrophobia, metallic implants or pacemak-
ers, and diminished access to the patient), the relative inexperience in
some practitioners in interpreting MRI scans in acute stroke, and cost-
effectiveness102 work in CT’s favor for this indication. Therefore, in the
vast majority of EDs, a non–contrast-enhanced CT is the most readily
available imaging study and is the only imaging study necessary prior
to administration of thrombolytics.19 An emerging exception to this
general rule is in the case of patients in whom time of stroke symptom
onset is uncertain. One trial found that patients with ischemic stroke seen
with diffusion-weighted MRI, but no hyperintensity of the parenchyma
seen on fluid-attenuated inversion recovery, benefited from IV thrombo-
lytic therapy104 (see later section “Thrombolysis: Indications, Exclusions,
Dosage, and Complications”). Nevertheless, even in these patients, non–
contrast-enhanced CT is still the imaging mode of first choice.
! VASCULAR IMAGING
With the advent of endovascular therapies, identifying the presence of
intracranial large-vessel stenosis or occlusion is important for therapeutic
decisions. CT angiography or magnetic resonance angiography can detect
these lesions. If a patient is a possible candidate for endovascular therapy,
vascular imaging (typically CT angiography of the head and neck) is rec-
ommended concurrently with the initial head CT; however, these
additional studies should not delay thrombolytic administration.19 In
other words, if a patient is a candidate based on the initial CT, do not
delay thrombolytic administration while waiting to perform CT angi-
ography or to receive the results of CT angiography. Therefore, if an
 CHAPTER 167: Stroke Syndromes 1127

TABLE 167-7 Core ED Interventions for Suspected Acute Stroke

Intervention/Evaluation
All patients
Assessment of airway, breathing,
circulation
Establish IV access
Pulse oximetry
Oxygen administration (if hypoxia
is present)
Cardiac monitoring
Bedside glucose determination
Noncontrasted brain CT or MRI
ECG
CBC including platelet count
Coagulation studies
Electrolyte levels
Cardiac biomarker levels
Nothing by mouth (NPO) order
Strict bed rest in the ED
Selected patients
Chest radiograph
Urinalysis
Pregnancy test (if female of
childbearing age)
Toxicology screen and/or blood alcohol
level (if ingestion suspected)
Lumbar puncture (if infection or
subarachnoid hemorrhage suspected)
Rationale/Discussion
Immediate life threats must be addressed before other interventions are undertaken. Actively manage airway if necessary.
IV access is necessary for possible thrombolytic therapy. (Do not delay brain imaging for prolonged IV access attempts.)
To detect hypoxia.
Routine oxygen supplementation is not indicated in stroke86 and should be given only to keep oxygen saturation >94%.
Dysrhythmias, especially atrial fibrillation, are not infrequent in acute stroke and may predict 3-month mortality.87,88 Prophylactic administration
of antiarrhythmic agents is not indicated.
To rapidly rule out hypoglycemia mimicking stroke. Treat hypoglycemia (<60 milligrams/dL) with IV dextrose.
This is the only laboratory test result required prior to thrombolytic therapy19 unless the patient is taking oral anticoagulation therapy or
heparin, or if there is a strong suspicion of thrombocytopenia or other bleeding diatheses19 (see Table 167-11).
To exclude intracerebral hemorrhage, other contraindications to IV thrombolytics, or stroke mimics. (See discussion in “Brain Imaging” section
of this chapter.)
Acute coronary syndrome, dysrhythmias (especially atrial fibrillation), ECG changes, and abnormal cardiac biomarkers are frequently associated
with acute stroke.89,90 ECG abnormalities and abnormal troponin T levels may also predict short-term and 3-mo mortality.87,91 A large study
(n = 9180) of consecutive stroke patients revealed that 2.3% suffered a subsequent myocardial infarction, with 64.9% morbidity/mortality
compared with 35.8% in the entire cohort.92 A 2016 meta-analysis (n = 52,098) determined that one third of ischemic stroke patients with no
previous cardiac history had >50% coronary stenosis. There was also a 3% overall risk of having an myocadiac infarction within a year of an
acute stroke.93
To detect polycythemia, thrombocytosis, or thrombocytopenia.
To detect preexisting coagulopathy in hemorrhagic stroke or when thrombolytics are being considered in circumstances where there is a
strong suspicion of the possibility of a coagulopathy (see Table 167-11).
To detect electrolyte-imbalance stroke mimics (particularly Na+ and Ca2+).
See “ECG” earlier in this table. A 2018 study also found that an elevated B-type natriuretic peptide within 48 hours was associated with a pure
cardiac stroke mechanism (odds ratio 4.35; 95% confidence interval 2.59–7.29; P < .5) and may be useful in detecting cardiac etiologies of
ischemic stroke.94
To protect against aspiration.
To protect against falls and seizures (in the period immediately after stroke). In patients who can maintain oxygenation, supine position has
been suggested to possibly improve patient outcomes by enhancing cerebral blood flow95; however, a large (n = 11,093) cluster-randomized,
crossover trial found no difference in stroke patient outcomes between lying flat for 24 hours and head of bed elevation to at least
30 degrees.96 However, significant methodologic concerns about this study have been raised, and optimal head positioning for stroke remains
controversial.97 That said, it is probably reasonable to consider raising the head of the bed to 15 to 30 degrees in patients at risk for hypoxia,
airway compromise, aspiration, or suspected increased intracranial pressure.
Routine chest radiography in asymptomatic patients is not recommended and should be reserved only for situations where a cardiopulmonary
contraindication to thrombolytics is suspected or if immediate management would be significantly impacted by chest radiograph findings.98
To detect infectious stroke mimics or stroke-associated infections.
Pregnancy influences diagnosis and management considerations.
To detect stroke mimics as well as potential causes of stroke such as ingestion of a sympathomimetic (e.g., cocaine, methamphetamine,
phencyclidine).
To detect stroke mimics. 2018 American Heart Association/American Stroke Association guidelines recommend that based on consensus
expert opinion (Class IIb; Level of evidence: C-EO), IV thrombolysis may be considered in patients who have undergone lumbar puncture in the
preceding 7 d.19

indicated CT angiography is not done with the initial head CT, it is have a serum creatinine result prior to performing contrasted studies
reasonable to administer thrombolytics after the noncontrasted CT for stroke, because these studies are not associated with significantly
and then return the patient to the CT scanner for CT angiography increased risk of acute kidney injury.105-107
to minimize door-to-needle time.19 It is important to realize that in
patients with no history of renal insufficiency, it is not necessary to ! PERFUSION STUDIES
TABLE 167-8 AHA/ASA Time Recommendations for Acute Ischemic Stroke In acute ischemic stroke, the area of irreversible brain infarct (core)
Presenting to the ED is surrounded by ischemic tissue that may potentially be salvageable,
regardless of the time of onset of symptoms. The size of this penumbra
Intervention Time Goal (from ED arrival) region cannot be ascertained clinically, so perfusion CT and diffusion-
Activation of stroke team Immediately upon arrival weighted MRI/fluid-attenuated inversion recovery can be used to mea-
Start of brain imaging ≤20 minutes sure the size of the penumbra and to guide further therapy for patients
who fall outside the time ranges for thrombolysis or where the time of
Administration of IV thrombolytics ≤60 minutes (secondary goal ≤45 minutes) symptom onset is unclear.108 However, to date, there are only two
Abbreviation: AHA/ASA = American Heart Association/American Stroke Association. major positive studies in these particular patients that used perfusion
1128 SECTION 14: Neurology
studies to select candidates for endovascular therapy in their protocols
(see later section “Endovascular Therapy”): the Diffusion-Weighted
Imaging or Computerized Tomography Perfusion Assessment with
Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes
Undergoing Neurointervention (DAWN) trial109 and the Diffusion and
Perfusion Imaging Evaluation for Understanding Stroke Evolution trial
(DEFUSE 3).110 Therefore, the current AHA/ASA guidelines do not
recommend routine use of perfusion studies in all stroke patients.
Rather, they primarily advocate using perfusion studies in the context
of strict adherence to DAWN and DEFUSE 3’s inclusion and exclusion
criteria when treating patients outside of clinical trials.19 This point has
become an issue of debate because of the publication of positive studies on
patients who awaken with stroke symptoms (“wake-up strokes”) that used
CT perfusion to aid in selecting patients for thrombolytic therapy.104,111,112
These studies and clinician feedback caused the AHA/ASA to withdraw
the portion of their 2018 guidelines that suggested using perfusion stud-
ies in selecting patients for endovascular therapy in <6 hours was not
beneficial.22 Therefore, at this time, the best use of perfusion studies in
acute stroke remains somewhat unsettled, but it is likely to be pivotal in
the management of patients with unknown or prolonged last known well
times113 and in patients with TIA (see later section “TIA Risk Stratification
and Disposition”).
! GENERAL TREATMENT OF
ACUTE ISCHEMIC STROKE
STANDARD TREATMENT
Initial ED stabilization and interventions are listed in Table 167-7.19,86-98
Many of these interventions are consensus based. Not all patients will be
eligible for thrombolytics, so it is important to follow general treatment
principles for all patients.
Dehydration can contribute to worsened outcomes in ischemic stroke
patients secondary to increased blood viscosity, hypotension, renal impair-
ment, and venous thromboembolism.114,115 However, routine volume
expansion and hemodilution do not improve outcomes in stroke patients.116
Therefore, correct dehydration if present with IV crystalloid fluids, but do
not overcorrect. For euvolemic patients, provide maintenance fluids.
Routine oxygen supplementation is not indicated in stroke86 and
should be given only if necessary to keep oxygen saturation >94%.
Hyperbaric oxygenation treatment is of no benefit.117
Fever is associated with increased morbidity and mortality in stroke,118
possibly due to fever-related inflammatory response,118 increased meta-
bolic demands, and free radical production.119 Identify the source of
fever and treat the underlying cause (e.g., infection). While it is tradi-
tional to treat the fever itself with acetaminophen, strong evidence of
favorable outcomes as a result of doing this remains elusive.120,121 Avoid
ibuprofen for temperature regulation, as it has been shown to not lower
temperature in these patients122 and may be associated with risk of
bleeding. In addition, physical cooling measures should be considered
second-line therapies only,123 as their benefit has not been established.124
Admit all acute stroke patients to monitored care units familiar with
the care of stroke patients, preferably to specialized stroke units at des-
ignated stroke centers. The use of stroke units has been associated with
decreased complications and length of stay, improved daily function,
decreased rate of discharge to long-term care facilities, and increased
likelihood of being able to live at home in the long term—with the benefit
being independent of thrombolytic use.125-127 If a patient with acute stroke
presents to a facility that lacks these resources, consider transferring the
patient to a higher level of care after the patient’s condition has stabilized
and IV thrombolytics have been given, as indicated—the “drip and ship”
model. Emergent, early consultation with an experienced stroke physi-
cian at the accepting institution is desirable in these circumstances.
BLOOD PRESSURE CONTROL IN STROKE
The optimal blood pressure for acute ischemic stroke victims is
unknown; however, based on consensus opinion, the current AHA/ASA
acute stroke guidelines19 recommend that hypotension and hypovolemia
TABLE 167-9 Management of Hypertension Before Administration of
Recombinant Tissue Plasminogen Activator (rtPA) or in Patients
Awaiting Thrombectomy
If the patient is a candidate for rtPA therapy, the target arterial blood pressures are
systolic blood pressure ≤185 mm Hg and diastolic blood pressure ≤110 mm Hg.
Drug Comments
Labetalol, 10–20 milligrams Use with caution in patients with severe asthma, severe
IV over 1–2 min, may repeat ×1 chronic obstructive pulmonary disease, congestive heart
failure, diabetes mellitus, myasthenia gravis, concurrent
calcium channel blocker use, hepatic insufficiency.
May cause dizziness and nausea.
or
Nicardipine infusion, Use with caution in patients with myocardial
5 milligrams/h, titrate up by ischemia, concurrent use of fentanyl (hypotension),
2.5 milligrams/h at 5- to congestive heart failure, hypertrophic cardiomyopathy,
15-min intervals; maximum portal hypertension, renal insufficiency, hepatic
dose: 15 milligrams/h; when insufficiency (may need to adjust starting dose).
desired blood pressure attained, Contraindicated in patients with severe aortic
reduce to 3 milligrams/h stenosis. Can cause headache, flushing, dizziness,
nausea, reflex tachycardia.
or
Clevidipine infusion,
1–2 milligrams/h, titrate up
Use with caution in patients with congestive
heart failure. Can cause reflex tachycardia atrial
by doubling dose every fibrillation, and systemic hypotension. Contraindicated
2–5 min; maximum dose: in patients with severe aortic stenosis, allergies
21 milligrams/h to soy or eggs, and lipid metabolism disorders
(e.g., pathologic hyperlipidemia, lipoid nephrosis, or
acute pancreatitis with hyperlipidemia).
Alternative agents such as hydralazine or enalaprilat may be considered if clinically
appropriate.
If the target arterial blood pressures for rtPA administration cannot be reached with these
initial measures, then the patient is no longer a candidate for rtPA therapy.
be corrected with either colloids or crystalloids128 to maintain organ
perfusion; however, there is no specific target blood pressure for patients
not eligible for reperfusion therapy.
Conversely, based on the blood pressure guidelines used in
randomized controlled trials of thrombolytics, blood pressure control
is considered essential prior to, during, and after thrombolytic therapy.
A systolic blood pressure >185 mm Hg or a diastolic blood pressure
>110 mm Hg is a contraindication to the use of thrombolytics19 because
elevated blood pressure (both before and after thrombolysis)129,130
is associated with increased risk for hemorrhagic transformation of
ischemic stroke. Elevated pretreatment blood pressure is common
(20%),131 and a strategy of active management of elevated blood
pressure as opposed to watchful waiting may increase the proportion
of patients able to receive thrombolysis.131,132 Therefore, if a patient
is a candidate for thrombolytics, lower blood pressure to meet
these entry parameters. An approach to management of arterial
hypertension is detailed in Table 167-919 and Table 167-10.19 If
the target arterial blood pressures cannot be reached with these
measures, then the patient is no longer a candidate for thrombolytic
therapy. Similarly, based on randomized controlled trials of intra-
arterial therapy, the same blood pressure goal of ≤185/110 mm Hg
is recommended for those who are candidates for intra-arterial
therapy.19 Preliminary studies also suggest that less favorable outcomes
after thrombectomy are also associated with elevated baseline blood
pressures.133
HYPERGLYCEMIA
The current AHA/ASA guidelines recommend the maintenance of blood
glucose between 140 milligrams/dL (7.77 mmol/L) and 180 milligrams/dL
(9.99 mmol/L).19 Avoid and treat hypoglycemia (<60 milligrams/dL

TABLE 167-10 Management of Hypertension During and After Administration
of Thrombolytics or Other Acute Reperfusion Therapy
Blood Pressure Monitoring Frequencies
Time After Start of rtPA Infusion Frequency of Blood Pressure Monitoring
0–2 h Every 15 min
3–8 h Every 30 min
9–24 h Every 60 min
Drug Treatment of Hypertension During and After Administration of Thrombolytics
or Other Acute Reperfusion Therapy
If systolic blood pressure is Labetalol, 10 milligrams IV followed by infusion
>180–230 mm Hg or diastolic at 2–8 milligrams/min.
blood pressure is >105–120 mm Hg or
Nicardipine infusion, 5 milligrams/h, titrate up
by 2.5 milligrams/h at 5- to 15-min intervals;
maximum dose 15 milligrams/h.
or
Clevidipine infusion, 1–2 milligrams/h, titrate
up by doubling dose every 2–5 min; maximum
dose 21 milligrams/h.
If blood pressure is not controlled by Consider sodium nitroprusside infusion
above measures or if diastolic blood (0.5–10 micrograms/kg/min). Continuous
pressure >140 mm Hg arterial monitoring advised; use with caution
in patients with hepatic or renal insufficiency.
Increases intracranial pressure. Pregnancy
category C.
[3.33 mmol/L]). Remember that both hypoglycemia and hyperglycemia
are important stroke mimics.
Hyperglycemia is common in acute stroke,134,135 and glycemic con-
trol has been recommended based on data that associate less favorable
outcomes with hyperglycemia.136-138 However, data to support improved
outcomes with tight glycemic control are lacking,139,140 and hypoglycemia
must be avoided because it is associated with brain dysfunction.140
ANTIPLATELET THERAPY
The current AHA/ASA guidelines recommend the adminis-
tration of oral (or by rectum if swallowing impairment is pres-
ent) aspirin within 24 to 48 hours after stroke onset unless
thrombolytics have been given within the prior 24 hours.19 No
antiplatelet agent (including aspirin) should be given within 24
hours of receiving thrombolytic therapy. When the results
of the International Stroke Trial141 and the Chinese Acute Stroke
Trial142 are combined (40,000 patients), these studies demonstrate
significant reduction in mortality and morbidity rates (at 4 weeks and
6 months) when aspirin (dose 160 to 300 milligrams) is administered
to acute ischemic stroke patients within 48 hours.143 The benefit seems
due mainly to reduction of recurrent stroke. Aspirin is cost-effective and
adds no risk to the outcome of ischemic stroke.143 In eligible patients
with aspirin contraindications, it might be reasonable to consider alter-
native antiplatelet drugs, but evidence for their efficacy is limited.19 In
terms of combination antiplatelet therapy, the Clopidogrel in High-Risk
Patients With Acute Nondisabling Cerebrovascular Events (CHANCE)
trial found that mild stroke patients who received clopidogrel along
with aspirin within 24 hours had fewer recurrent strokes (hazard ratio
0.68; 95% confidence interval [CI], 0.57 to 0.81; number needed to
treat = 29)144,145 and better functional outcomes (1.7% absolute reduction
of poor functional outcome; 95% CI, 0.03% to 3.42%; number needed
to treat = 59)146 in 90 days than patients who received aspirin alone.
However, the CHANCE study patients had mild, nondisabling strokes or
TIAs, and the study was performed entirely in China. Therefore, these
results await wider external validation before they can be recommended
routinely. Antiplatelet therapy is contraindicated in acute hemor-
rhagic stroke.
CHAPTER 167: Stroke Syndromes 1129
! THROMBOLYSIS BACKGROUND
NINDS STUDY
The National Institutes of Health/NINDS study147 was a randomized
double-blind trial comparing IV alteplase with placebo. The drug was
administered within 3 hours of symptom onset, with approximately one
half of patients treated within 90 minutes. Outcomes were measured using
four different neurologic outcome scales (including the NIHSS) and a
global statistic. Although there was no difference in the treatment and
control groups at 24 hours, at 3 months, the odds ratio (OR) for a favorable
outcome in treated patients was 1.7 (95% CI, 1.2 to 2.61; P = .008), an 11%
to 13% absolute risk reduction benefit (number needed to treat = 8 to 9
for tPA <3 hours). Put another way, 31% to 50% of the patients receiving
alteplase (depending on the scale used) had a favorable outcome at 3 months
compared with 20% to 38% of patients given placebo. Benefit was found
regardless of ischemic stroke subtype and was sustained 1 year after therapy.
Symptomatic intracerebral hemorrhage attributable to thrombolytics
occurred in 6.4% of patients in the alteplase group (45% mortality), whereas
symptomatic intracerebral hemorrhage occurred in 0.6% of those in the
placebo group (50% mortality). Despite this increased rate of intracerebral
hemorrhage, the mortality rate at 3 months was not significantly different
for the treatment and placebo groups (17% vs. 21%, respectively; P = .30),
and the percentage of patients left severely disabled was lower among
those receiving thrombolytics.147 The NINDS trial represented the first
randomized placebo-controlled trial that showed benefit of IV alteplase
in acute stroke. Prior trials using different thrombolytic agents, different
dosing of thrombolytics, or different treatment windows failed to show
benefit or showed harm. Based largely on the NINDS data, in 1996, the
U.S. Food and Drug Administration approved the use of IV alteplase in
acute ischemic stroke within 3 hours of stroke onset.
Concerns have been raised about the NINDS trial results.148,149 The
NINDS trial, although well designed, was relatively small and studied
624 patients total, 312 of whom received alteplase. As a result of chance,
there existed an imbalance in baseline stroke severity between the two
groups that apparently favored the thrombolytic group. Therefore, the
NINDS investigators commissioned an independent reanalysis of the
data150 in 2004 that took this imbalance into account. This reanalysis
found that, despite the imbalance, the originally described benefit of
alteplase held. The authors concluded that “these findings support the
use of alteplase to treat patients with acute ischemic stroke within 3
hours of onset.”150 However, they did concede the need to collect further
data to determine which particular stroke subgroups would benefit or
be harmed. In 2009, a graphic reanalysis of the NINDS trial data set was
published,151 which showed very small differences in the treatment and
placebo group outcomes, with a slight favoring of thrombolytic treat-
ment. Therefore, the authors concluded that the reported NINDS results
could have resulted from confounding alone. However, the methodology
of this reanalysis was challenged in a subsequent graphic reanalysis of
the NINDS data that supported the original results,152 although these cri-
tiques have also been challenged in turn.153 Finally, the reliability of one
of the primary measures of stroke disability in NINDS and subsequent
trials, the modified Rankin scale, has been questioned.154
SUBSEQUENT THROMBOLYTIC TRIALS
The European Cooperative Acute Stroke Study III (ECASS III) demon-
strated efficacy with an expansion of the treatment window to 4.5 hours.31
The OR favored treated patients (OR 1.34; 95% CI, 1.02 to 1.76), and
the post hoc analysis, which adjusted for confounding variables, yielded
similar statistical results (OR 1.42; 95% CI, 1.02 to 1.98). Although the
incidence of intracerebral hemorrhage was higher in the treated group
than the placebo group (27% vs. 17%) and the incidence of symptomatic
hemorrhage was also higher in the treated group (2.4% vs. 0.2%; 7.9% vs.
3.5% when the NINDS definition of symptomatic hemorrhage was used),
mortality was similar in both groups (7.7% in the rtPA group and 8.4% in
the control group). Based on these data, AHA/ASA issued a 2009 scientific
advisory155 that recommended thrombolytics should be administered to
eligible patients who present between 3 and 4.5 hours of an acute stroke,
as long as they meet the ECASS III criteria (see Table 167-11). However,
1130 SECTION 14: Neurology
TABLE 167-11 Summary of American Heart Association (AHA)/American Stroke Association (ASA) 2018 Inclusion/Exclusion Criteria for IV Alteplase in Acute
Ischemic Stroke
Inclusion Criteria
Onset of symptoms <3 h prior to thrombolytic administration
Measurable diagnosis of acute ischemic stroke
Age ≥18 y
Onset of symptoms from 3 to 4.5 h prior to rtPA administration
Exclusion Criteria
Last known well time >3 or 4.5 hours
Acute intercranial hemorrhage or history of intracranial hemorrhage
Symptoms and signs suggestive of subarachnoid hemorrhage
CT brain imaging that exhibits extensive regions of clear hypoattenuation (obvious hypodensity)
Prior ischemic stroke or severe head trauma within 3 months
Acute posttraumatic brain infarction that occurs during acute in-hospital phase
Intracranial/intraspinal surgery within 3 months
GI malignancy or GI bleeding within 21 days
Pretreatment systolic blood pressure >185 mm Hg or diastolic blood pressure >110 mm Hg despite therapy (see Table 167-9)
Platelet count <100,000/mm3
INR >1.7 or activated PTT >40 s, or prothrombin time >15 s
Use of low-molecular-weight heparin within preceding 48 h
Current use of direct thrombin inhibitors or direct factor Xa inhibitors with
elevated sensitive laboratory tests (such as activated PTT, INR, platelet count,
and ecarin clotting time [ECT]; thrombin time; or appropriate factor Xa activity
assays)
Current use of glycoprotein IIb/IIIa receptor inhibitors
Current infective endocarditis
Known or suspected aortic arch dissection
Intra-axial intracranial neoplasm
Blood glucose level <50 milligrams/dL (2.7 mmol/L)
Selected Additional Recommendations for Various Conditions
Arterial puncture of noncompressible artery <7 d
Arteriovenous malformation
Dural puncture
Eye hemorrhage
Major surgery or major trauma (not involving the head) within preceding 14 d
Malignancy
Menstruation
Defined as the time the patient was last known well or last known to be at their neurologic
baseline.
Use of NIHSS score recommended. There is no upper or lower limit of NIHSS score for thrombolytics,
as benefit may be seen with both mild but disabling stroke symptoms170 as well as in very severe
strokes.158 Early improvement with residual moderate impairment and potential disability is not a
contraindication.
No upper age limit for <3 h last known well time administration.
Must meet the above inclusion criteria, plus these additional inclusion criteria:
Age ≤80 y
No history of diabetes mellitus and prior stroke
NIHSS score ≤25
Not taking oral anticoagulants
No brain imaging evidence of ischemic injury involving greater than one third of the middle cerebral
artery territory
If patient has no history of thrombocytopenia, thrombolytics may be given before this lab result is
available; however, stop thrombolytics if the platelet count is <100,000/mm3.
If patient is not taking oral anticoagulant or heparin, thrombolytics may be given before this lab
result is available; however, stop thrombolytics if these lab tests come back elevated above normal
limits.
Oral anticoagulant use in and of itself is not a contraindication, but these labs should be checked
prior to administration of thrombolytics if the patient is taking oral anticoagulants or heparin.
Thrombolytics may be given before coagulopathy labs results available if the patient has not
received a dose of these agents for >48 h and if renal function is normal. Thrombolytics may be
given if the appropriate coagulopathy laboratory tests are not elevated.
The glucose level should be normalized prior to thrombolytic administration.
The safety and efficacy of thrombolytics in this condition are unclear.
The safety and efficacy of thrombolytics with this condition are unclear; however, thrombolytics
may be considered in the case of severe stroke with unruptured/untreated intracranial arteriove-
nous malformation.
Dural puncture (<7 d) is not a contraindication.
Diabetic retinal hemorrhage or other ophthalmologic hemorrhage is not a contraindication, but the
benefits of thrombolytics must be weighed against the potential threat to sight.
rtPA may be carefully considered if the benefits outweigh risks.
Extra-axial intracranial neoplasm is not a contraindication.
The safety and efficacy of thrombolytic administration in systemic malignancy are unclear.
Menstruation and menorrhagia without clinically significant anemia are not contraindications.
Clinically significant anemia due to these processes mandates an emergent consultation with a
gynecologist prior to thrombolytic administration
(Continued)
 CHAPTER 167: Stroke Syndromes 1131

TABLE 167-11 Summary of American Heart Association (AHA)/American Stroke Association (ASA) 2018 Inclusion/Exclusion Criteria for IV Alteplase in Acute
Ischemic Stroke (Continued)
Myocardial infarction Acute myocardial infarction is not a contraindication to rtPA.
Recent (<3 months) non–ST-segment elevation myocardial infarction is not a contraindication to rtPA.
Recent (<3 months) ST-segment elevation myocardial infarction involving the left anterior, right, or
inferior myocardium is not a contraindication to rtPA.
Other cardiac conditions Consult a cardiologist prior to rtPA administration for other cardiac conditions such as pericarditis,
heart chamber thromboses, and cardiac tumors.
Pregnancy rtPA may be considered for pregnant women with moderate to severe stroke. The administration of
rtPA at <14 d postpartum remains controversial.
Seizure at onset Seizure at onset is not a contraindication to rtPA if residual impairments are thought secondary to
stroke and not postictal phenomenon.
Unruptured intracranial aneurysm An aneurysm <10 mm in size is not a contraindication to rtPA.
rtPA administration with an aneurysm ≥10 mm size is controversial.
Abbreviation: NIHSS = National Institutes of Health Stroke Scale.

based on trial data and unpublished data from the U.S. manufacturer of
alteplase (Genentech), the U.S. Food and Drug Administration has denied
approval for this indication156; therefore, alteplase administration >3 hours
after symptom onset is still considered off label in the United States.157 In
contrast, the European Medicines Agency has approved use from 3 to 4.5
hours after symptom onset.
In 2012, the third International Stroke Trial (IST-3)158 was published,
making it the largest (n = 3035 patients) randomized controlled trial for
ischemic stroke to date. Patients in the treatment group were given the
standard dose of thrombolytics up to 6 hours after stroke onset, with
72% of patients receiving thrombolytics after 3 hours. The exclusion
criteria were loosened, including eliminating any upper age limit and the
broadening of the acceptable blood pressure range prior to thrombolytics
(systolic 90 to 220 mm Hg; diastolic 40 to 130 mm Hg).159 The trial
showed no difference at 6 months in the primary outcome measure,
Oxford Handicap Score (0 to 2; alive and independent): 37% versus 34%
(OR 1.13; 95% CI, 0.95 to 1.35; P = .181) in the treatment versus control
groups, respectively. However, a secondary ordinal analysis showed a
favorable shift in Oxford Handicap Scores (indicating less disability) in
the treatment group at 6 months. Although symptomatic intracranial
hemorrhage occurred in 7% of treated patients versus 1% of controls (P
<.0001) and 11% of deaths occurred within 7 days in treated patients
versus 7% in controls (P <.001), mortality at 6 months was the same
(27%) in both treatment and control groups. The favorable shift in Oxford
Handicap Score in treated patients appeared to last at least 18 months and
was associated with higher overall self-reported health, with no increased
mortality.160 Interestingly, a subgroup analysis in the IST-3 revealed that
patients receiving thrombolytics between 3 and 4.5 hours after symptom
onset actually had a nonstatistical trend toward a worse functional
outcome compared with controls than patients receiving thrombolytics
less than 3 hours and from 4.5 to 6 hours after symptom onset.158
In 2014, a Cochrane systematic review and meta-analysis (27 trials,
10,187 patients) concluded that thrombolytic-treated stroke patients
were less likely to be dead or dependent than controls, and that early
treatment was better than late treatment, with possible benefit up to
6 hours after symptom onset.161 This benefit held despite increased
symptomatic intracranial hemorrhage and more early and late deaths.
In 2016, a group of nonneurologists and nonemergency physicians pub-
lished a systematic review and meta-analysis (26 trials, 10,431 patients)
that concluded that although thrombolysis was associated with margin-
ally improved functional outcomes, it also increased early mortality and
symptomatic intracranial hemorrhage rates.154,162 These authors urgently
called for further randomized controlled trials to be performed to help
resolve this continuing controversy.
In 2015, the American College of Emergency Physicians gave a Level B
(moderate clinical certainty) recommendation for IV thrombolytics both
in the below 3 hour and in the 3 to 4.5 hour treatment windows.163 Sub-
sequently, although the Canadian Association of Emergency Physicians
“strongly recommended” IV thrombolytics in the below 3 hour window, as
a result of data from the IST-3158 and other data,164 the Canadian Association
of Emergency Physicians issued a conditional recommendation against the
use of thrombolytic therapy beyond 3 hours of symptom onset.165 Others
recently raised similar concerns,149,166 some of which prompted a review
of alteplase for ischemic stroke by the United Kingdom Medicines and
Healthcare Products Regulatory Agency. This review eventually upheld
the decision to endorse the use of IV alteplase for stroke up to 4.5 hours.167
! THROMBOLYSIS: INDICATIONS,
EXCLUSIONS, DOSAGE,
MONITORING, AND COMPLICATIONS
Indications The decision to administer thrombolytics must be made
rapidly and accurately. There must be careful identification of the time
of symptom onset, defined as the last moment the patient was known
to be at baseline (i.e., last known well time). Taking the patient and
family chronologically through the events immediately prior to the
stroke is particularly helpful in unclear cases. Thrombolytic use in
stroke is not currently recommended by AHA/ASA when the time of
onset cannot be reliably determined.
As of this writing, the AHA/ASA recommend that strokes rec-
ognized upon awakening (up to approximately 25% to 30% of
strokes168,169) should be clocked from the time at which the patient
was last known to be without symptoms. However, after the current
AHA/ASA guidelines19 were published, the landmark Efficacy and
Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP)
trial results were published.104 WAKE-UP was a randomized con-
trolled multicenter European trial that recruited patients who awoke
with stroke symptoms or who were not considered candidates for IV
thrombolysis with a last known well time of >4.5 hours. These patients
underwent MRI with diffusion-weighted imaging and fluid-attenuated
inversion recovery. If in the judgment of the treating physician, there
was evidence of an acute ischemic stroke on diffusion-weighted MRI,
but no parenchymal hyperintensity on fluid-attenuated inversion recov-
ery, the patients were considered to have a diffusion-weighted imag-
ing–fluid-attenuated inversion recovery mismatch consistent with a
recent stroke and the patients were offered enrollment into the study.
A total of 503 patients were randomly assigned to either a standard
dose of alteplase or placebo, and there were no significant differences in
demographic qualities, stroke severity (median NIHSS of 6), or median
time of thrombolysis to symptom onset between the groups. Average
last known well time for both groups was about 10 hours, and the aver-
age time from symptom recognition to treatment was about 3 hours for
both groups. At 90 days after treatment, 53.3% of the alteplase group
had minimal disability (modified Rankin scale score of 0 or 1) compared
with 41.8% of the placebo group (adjusted OR 1.61; 95% CI, 1.09 to 2.36;
P = .02). The median 90-day modified Rankin scale score of the alteplase
group was 1, whereas in the placebo group, it was 2 (adjusted common
OR 1.62; 95% CI, 1.17 to 2.23; P = .003). However, 4.1% of patients who
received alteplase died within 90 days compared with 1.2% of patients
in the control group (OR 3.38; 95% CI, 0.92 to 12.52; P = .07), with 50%
of the deaths in the treatment group being unrelated to the acute stroke.
In a similar vein, 2.0% of the alteplase patients suffered a symptomatic
1132 SECTION 14: Neurology
intracerebral hemorrhage compared with 0.4% in the placebo group (OR
4.95; 95% CI, 0.57 to 42.87; P = .15). This trial had several limitations,
including the exclusion of patients eligible for mechanical thrombec-
tomy, adults >80 years old, and patients with NIHSS score of >25 and/
or large middle cerebral artery lesions. In addition, the trial was stopped
early (about 300 patients short of planned enrollment) due to cessation
of funding. Had these limitations not been present, the numerical trends
toward increased harm in the treatment group may well have been
statistically significant. Although these important results await further
confirmation by larger trials, WAKE-UP is a landmark trial that has the
potential to change practice in the near future, especially when mechani-
cal thrombectomy is not a viable option; however, its results should be
considered preliminary at this time.
To achieve optimal outcomes, the patient must be evaluated carefully
for indications and exclusions for IV thrombolytic therapy (Table 167-11),
and the findings must be documented meticulously, preferably on
computerized or preprinted assessment forms. The decision to admin-
ister thrombolytics is made by assessing multiple factors, including the
numerical NIHSS score. A score between 4 and 22 is commonly used
as one of the criteria for thrombolytic administration. However, some
patients may have a lower NIHSS score, yet have a potentially disabling
condition (e.g., aphasia, hemianopia, gait disturbance). Some studies
have also shown benefit with thrombolysis in minor strokes,170,171 but
further data are needed to be conclusive.172,173 Nevertheless, interpret an
NIHSS score in the total context of the individual patient when making
treatment decisions.
A bedside blood glucose is required prior to thrombolysis; how-
ever, do not withhold thrombolysis because other laboratory results
are still pending unless there is reason to suspect a pathologic or
iatrogenic coagulopathy. Administer thrombolytic therapy to eligible
patients even if endovascular therapies are being considered.19
Exclusions In the previous AHA/ASA stroke guidelines,155,174 the exclu-
sion criteria hewed very closely to the conservative criteria used by the
NINDS and ECASS III trials. However, in the current recommenda-
tions,19 several of the previous exclusion/relative exclusion criteria from
the 2013 guidelines156 have been eliminated or modified based on recent
data and expert consensus.157 In addition, the practical clinical validity of the
ECASS III criteria for administration of thrombolytics from 3 to 4.5 hours
has been challenged, because positive outcomes have been demonstrated
in patients who would not have qualified for treatment in ECASS III.157
However, the current AHA/ASA guidelines still list them as part of the
inclusion criteria for thrombolytics from 3 to 4.5 hours (Table 167-11),
but they note the ongoing controversy. Therefore, carefully consider the
treatment risks versus anticipated benefits of proposed rtPA therapy,
especially if any of the relative contraindications are present prior to
administration of the drug. When faced with such patients, obtain emer-
gency consultation with a physician with acute stroke expertise, whether
on-site or via telemedicine, because local expert treatment varies and
patient care decisions should be individualized.
Dosage As of this writing, only alteplase is FDA approved for treatment
of acute ischemic stroke. However, the treatment options may include
tenecteplase in some situations, especially outside the US. Alteplase
and tenecteplase have different dosages. Therefore, use the full brand or
generic name (alteplase, tenecteplase) when ordering. Do not use abbre-
viations (rtPA, TNK, etc) to avoid medication errors. As doses also vary
for the clinical indication (stroke, STEMI, PE), make sure the dose you
select is the dose appropriate for the clinical indication.175 The standard
total dose of alteplase is 0.9 milligram/kg IV, with a maximum dose of
90 milligrams; administer 10% of the dose as a bolus over 1 minute,
with the remaining amount infused over 60 minutes. Recent data from
Asian trials have suggested that low-dose alteplase in acute ischemic
stroke results in comparable patient outcomes, with less morbidity and
mortality.176 However, at the time of this writing, these preliminary results
await large-scale confirmation in non-Asian populations; therefore, the
above standard alteplase dose remains recommended.
The dose of tenecteplase is weight-based,: <60 kg: 30 milligrams;
60-70 kg: 40 milligrams; 80-90 kg 45 milligrams; >90 kg, 50 milligrams
for patients > 90 kg. The maximum dose is 50 milligrams. Tenecteplase
is given as a single IV bolus over 5-10 seconds.
Monitoring and Complications Perform blood pressure and neu-
rologic checks every 15 minutes for 2 hours after starting the infusion.
Table 167-10 outlines the emergent management of hypertension during
and after administration of thrombolytics. Admit patients to a specialized
stroke unit (if available) or an intensive care unit familiar with the use of
thrombolytic drugs and neurologic monitoring. If post-rtPA bleeding
is suspected, halt drug administration and perform an emergent CT.
Order a CBC with platelet count, coagulation studies, fibrinogen level,
and typing and cross-match for packed red blood cells, cryoprecipitate
or fresh frozen plasma, and platelets. Emergent neurology, neurosurgery,
and hematology consultations, as needed, are appropriate. Be prepared
to treat the possible side effect of orolingual angioedema (reported
incidence approximately 0.2% to 17%).177-179 Patients taking angiotensin-
converting enzyme inhibitors appear to be at higher risk for this com-
plication (adjusted OR 3.9; 95% CI, 1.6 to 9.7).180 Middle cerebral artery
infarction has also been previously reported to be a risk factor, but this
has been challenged by more recent data.181 If orolingual angioedema
occurs, discontinue thrombolysis19 and treat angioedema similarly to
other causes of angioedema (see Chapter 14, “Allergy and Anaphylaxis”).
Consider administration of icatibant, which has been reported to be
efficacious in thrombolytic-associated angioedema in a handful of case
reports.182,183 Administration of plasma-derived C1 esterase inhibitor has
also been suggested to be of value, given its efficacy in angiotensin-con-
verting enzyme inhibitor–associated angioedema.19,184 The role of angio-
edema prophylaxis in this setting is unknown, but there has been at least
one reported case of successful IV thrombolysis for recurrent stroke in
a patient with history of previous thrombolytic-associated angioedema,
using simultaneous administration of prednisolone, ranitidine, and clem-
astine.185 History of angioedema to thrombolytics and use of angiotensin-
converting enzyme inhibitors are not designated by the ASA/AHA as
explicit contraindications to IV thrombolysis19; however, if these factors
are present, specifically discuss them as part of informed consent.
! ENDOVASCULAR THERAPY
There is intense interest in endovascular therapies, primarily intra-arterial
thrombolysis and mechanical clot disruption/extraction. Potential advan-
tages of endovascular therapies include an expanded treatment window,
a treatment for patients with non–time-based contraindications to IV
thrombolysis, an ability to specifically evaluate the occluded vascular
territory, use of lower total doses of thrombolytic drugs, and the pos-
sibility of mechanical clot disruption. However, early randomized trials
of mechanical endovascular therapy with primarily intra-arterial throm-
bolysis or first-generation endovascular devices did not show benefit.186-189
Subsequently, in 2015, five pivotal multicenter trials regarding intra-
arterial thrombectomy in acute ischemic stroke were published. The
Multicenter Randomized Clinical Trial of Endovascular Treatment for
Acute Ischemic Stroke in the Netherlands (MR CLEAN),190 the Extend-
ing the Time for Thrombolysis in Emergency Neurological Deficits–
Intra-Arterial (EXTEND-IA) trial,191 the Endovascular Treatment for
Small Core and Anterior Circulation Proximal Occlusion With Emphasis
on Minimizing CT to Recanalization Times (ESCAPE) trial,192 the Solitaire
FR With the Intention for Thrombectomy as Primary Endovascular
Treatment for Acute Ischemic Stroke (SWIFT PRIME) trial,193 and the
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 Eight Hours
of Symptom Onset (REVASCAT) trial194 were the first prospective,
randomized trials to demonstrate the efficacy of intra-arterial throm-
bectomy with IV thrombolysis with second-generation devices in acute
ischemic stroke. In 2016, an additional randomized trial, Thrombecto-
mie des Artères Cerebrales (THRACE),195 was published, the results of
which were consistent with those of the previous studies.
MR CLEAN190 was the largest trial (n = 502) and the only trial of this
group that was not stopped prematurely for efficacy. It compared intra-
arterial treatment (thrombolysis, thrombectomy, or both) with usual
medical therapy for patients with anterior circulation proximal occlu-
sions within 6 hours of stroke onset (91% of the control group received
IV rtPA). The inclusion criteria included adults >18 years old (no upper
 CHAPTER 167: Stroke Syndromes 1133

age limit) and an NIHSS score ≥2. Major findings included significant
90-day functional benefit in treatment versus controls (90-day modified
Rankin scale score of 0 to 2: 32.6% vs. 19.1%, respectively [OR 2.16;
95% CI, 1.39 to 3.38]; number needed to treat = 7). With intra-arterial
treatment, there was no significant increase in symptomatic ICH (7.7%
vs. 6.4%), but there was a higher incidence of vessel perforation (0.9%)
and dissection (1.7%), and 5.6% of patients had an ischemic stroke in a
different vascular distribution within 90 days versus 0.4% in controls.
However, despite these findings, there was no statistical difference in
mortality (18.9% vs. 18.4%). An important limitation of this study is that
although the disease severity was similar in the treatment and control
groups, the control group had relatively poor outcomes in terms of the
modified Rankin scale. This reflects the rather broad inclusion criteria
of the study, which may allow greater generalizability of the results.
The results of the other five trials cited are largely consistent with MR
CLEAN, and these trials were all stopped early during interim safety
analyses because of efficacy of the treatment arm (Table 167-12).
Based on the data from the previously discussed six trials, in 2015,
the AHA/ASA issued a new Class IA recommendation196 that patients
receive endovascular therapy with a stent retriever if they meet all of the
inclusion criteria in Table 167-13.
A subsequent pooled analysis (n =1287) for the first five random-
ized positive trials found that a modified Rankin scale score of 0 to 2
at 90 days was present in 46% of patients in the endovascular treatment
group versus 26.5% of controls (number needed to treat = 5.1), with no
significant difference in 90-day mortality or symptomatic intracranial
hemorrhage.197 A 2016 Cochrane systematic review and meta-analysis of
10 trials of endovascular therapy, including the previous negative trials,
concluded the following: “Moderate to high quality evidence suggests that
compared with medical care alone in a selected group of patients endo-
vascular thrombectomy as add-on to intravenous thrombolysis performed
within six to eight hours after large vessel ischaemic stroke in the anterior
circulation provides beneficial functional outcomes, without increased
detrimental effects.”198

TABLE 167-12 Results of Eight Positive Randomized Trials of Mechanical Intra-Arterial Treatment in Acute Anterior Stroke
Symptomatic
Intracranial
Mortality† Hemorrhage†
Upper Endovascular mRS (0–2) at 90 d* (treatment vs. (treatment vs.
Trial No. Age Limit (y) Treatment Time Inclusion Criteria (treatment vs. controls) controls) controls)
MR CLEAN190 502 None Retrievable stent Ability to undergo 32.6% vs. 19.1% 18.9% vs. 18.4% 7.7% vs. 6.4%
+/– intra-arterial endovascular treatment OR = 2.16 (95% CI,
thrombolysis or within 6 h 2.39–3.38)
intra-arterial NNT = 8
thrombolysis alone
EXTEND-IA191 70 None Solitaire FR stent IV thrombolysis 71% vs. 40% 9% vs. 20% 0% vs. 6%
retriever <4.5 h of stroke onset OR = 4.2 (95% CI, 1.4–12)
NNT = 4
ESCAPE192 316 None Retrievable stent Within 12 h of stroke 53% vs. 29.3% 10.4% vs. 19% 3.6% vs. 2.7%
onset Rate ratio = 1.8 (95% CI,
1.4–2.4)
NNT = 5
SWIFT PRIME193 196 80 Solitaire stent Within 6 h of 60% vs. 35% 9% vs. 12% 0% vs. 3%
retriever stroke onset Risk ratio = 1.70 (95% CI,
1.23–2.33)
NNT = 4
REVASCAT194 206 80 Solitaire stent Within 8 h of 43.7% vs. 28.2% 18.4% vs. 15.5% 1.9% vs. 1.9%
retriever stroke onset OR = 2.1 (95% CI, 1.1–4.0)
NNT = 7
THRACE195 414 80 Various stent IV thrombolysis within 53% vs. 42% 12% vs. 13% 2% vs. 2%
retriever devices 4 h and thrombectomy OR = 1.55 (95% CI,
within 5 h of stroke 1.05–2.30)
onset NNT = 9
DAWN109 206 None Trevo stent retriever Within 6–24 h of last 49% vs. 13% 19% vs. 18% 6% vs. 3%
known well time OR = 6.25 (95% CI,
3.11–12.54)
NNT = 3
DEFUSE 3110 182 90 Various FDA-approved Within 6–16 h of last 45% vs. 17% 14% vs. 26% 7% vs. 4%
thrombectomy devices known well time OR = 4.01 (95% CI,
2.02–8.02)
NNT = 4
Abbreviations: CI = confidence interval; DAWN = Diffusion-Weighted Imaging or Computerized Tomography Perfusion Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes
Undergoing Neurointervention; DEFUSE 3 = Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke; 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 Deficits–Intra-Arterial; FDA = U.S. Food and Drug Administration; MR CLEAN =
Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; mRS = modified Rankin scale; NNT = number needed to treat; OR = adjusted 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 Eight Hours of
Symptom Onset; SWIFT PRIME = Solitaire FR with the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke; THRACE = Thrombectomie des Artères Cerebrales.
∗
Treatment efficacy differences in each trial are statistically significant.
Differences in mortality and symptomatic intracranial hemorrhage in each trial were not statistically significant.
†
1134 SECTION 14: Neurology
TABLE 167-13 AHA/ASA Indications for Endovascular Therapy With a Stent
Retriever196
• Prestroke mRS score 0 to 1
• Acute ischemic stroke receiving IV rtPA within 4.5 h of onset according to guidelines
from professional medical societies
• Causative occlusion of the ICA or proximal MCA (M1)
• Age ≥18 y
• NIHSS score of ≥6
• ASPECTS of ≥6
• Treatment can be initiated (groin puncture) within 6 h of symptom onset
All 7 criteria need to be met for stent retriever endovascular therapy to be
indicated.
Abbreviations: AHA/ASA = American Heart Association/American Stroke Association; ASPECTS = Alberta
Stroke Program Early CT Score; ICA = internal carotid artery; MCA (M1) = sphenoidal (horizontal) segment
of the middle cerebral artery; mRS = modified Rankin scale; NIHSS = National Institutes of Health Stroke
Scale; rtPA = recombinant tissue plasminogen activator.
In 2018, two important studies, the DAWN trial109 (n = 206) and
the DEFUSE 3 trial110 (n = 182) compared endovascular therapy plus
standard treatment with standard treatment alone in patients with late
presenting stroke (6 to 24 hours and 6 to 16 hours last known well
time, respectively) and evidence of potentially reversible ischemia (a
mismatch between clinical symptoms and infarct size and a penumbra
of ≥15 mL, respectively; Table 167-12). Both trials were multicenter,
randomized, open-label trials with blinded outcome assessment, and
both were stopped early because of the loss of clinical equipoise in
favor of the treatment group. DAWN found that the percentage of
patients with functional outcome at 90 days (modified Rankin scale
score of 0 to 2) with thrombectomy was 49% compared with 13% in
the control group (an adjusted difference of 33% [95% CI, 21% to
44%]; posterior probability of superiority >0.999). Similarly, DEFUSE
3 found that thrombectomy patients had a better distribution of dis-
ability scores at 90 days than controls (OR 2.77; 95% CI, 1.63 to 4.70;
P <.001). The percentage of thrombectomy patients compared with
controls who had a modified Rankin scale score of 0 to 2 at 90 days
was 45% versus 17%, respectively (risk ratio 2.67; 95% CI, 1.60 to 4.48;
P <.001). In both trials, the mortality and morbidity outcomes in both
the treatment and control groups were statistically equal. Although
these results support the notion of extending the window for acute
treatment of stroke, an important caveat is that the AHA/ASA recom-
mends thrombectomy in the >6 hour window only if the strict inclu-
sion/exclusion criteria for DAWN or DEFUSE 3 are followed. The
inclusion and exclusion criteria of both trials are complex and lengthy
but are readily available online.199,200
Despite the encouraging results of all of these recent endovascular
therapy trials, the current availability of endovascular treatment modali-
ties remains rather limited at most primary stroke centers, which may
circumscribe widespread use.201
Nevertheless, although all eligible stroke patients should be consid-
ered for IV thrombolysis as a first-line therapy, also consider emergent
consultation with a neurointerventionalist for adjunctive endovascu-
lar therapy in patients who meet the criteria listed in Table 167-13196
and in patients who meet the DAWN or DEFUSE 3 criteria.199,200
! OTHER TREATMENT MODALITIES
Therapeutic hypothermia, induced hypertension, endovascular thera-
pies, carotid endarterectomy/stenting, and emergency hemicraniectomy
for massive infarcts are modalities that are being studied, but as of this
writing, benefits are unproven.
Mild therapeutic hypothermia is associated with improved neu-
rologic outcomes in comatose patients who survive cardiopulmonary
arrest.202 Consequently, there is much interest in the potential benefit
of induced hypothermia in acute stroke, both alone and in combination
with neuroprotective strategies203 and endovascular therapy.204 However,
hypothermia’s efficacy has not been firmly established, and it may be
associated with increased risk of pneumonia.205 Therefore, its use is con-
sidered experimental at this time.19
Animal data206 and preliminary trials have suggested that implement-
ing drug-induced hypertension in an effort to increase blood flow
to the ischemic penumbra may benefit outcomes from acute ischemic
stroke,207-209 with recent increased interest given penumbra-based endo-
vascular interventions.210 However, there are insufficient data to recom-
mend this modality outside of clinical trials at this time.19
Patients with a massive middle cerebral artery infarct are less favor-
able candidates for thrombolytic therapy and have an 80% mortality
rate. Massive middle cerebral artery infarct is commonly associated with
space-occupying cerebral edema and may be amenable to decompressive
craniectomy. A 2007 pooled analysis of data from three European trials
(Decompressive Surgery for the Treatment of Malignant Infarction of
the Middle Cerebral Artery [DECIMAL],211 Decompressive Surgery for
the Treatment of Malignant Infarction of the Middle Cerebral Artery
[DESTINY],212 and Hemicraniectomy After Middle Cerebral Artery
Infarction With Life-Threatening Edema Trial [HAMLET])213 showed
that decompressive hemicraniectomy was associated with better out-
comes than medical therapy.214 However, the overall efficacy of this
approach remains in question. For example, in 2014, the Hemicraniec-
tomy and Durotomy upon Deterioration Infarction-Related Swelling
(HeADDFIRST) pilot trial215 found no statistical difference in the
180-day mortality between the medically managed patients in this trial
(40%) and the patients who underwent hemicraniectomy plus medical
treatment (34%). Ultimately, several recent meta-analyses of hemicra-
niectomy versus medical treatment for large middle cerebral artery
infarction concluded that although decompressive craniectomy results
in reduced mortality, most survivors are left with severe or very severe
disability.216-218 Therefore, the decision to perform surgery must be made
on an individual case-by-case basis.
! TRANSIENT ISCHEMIC ATTACK
TIA is defined as follows: “a transient episode of neurological dysfunc-
tion caused by focal brain, spinal cord, or retinal ischemia, without acute
infarction.”219 This tissue-based definition recognizes that although TIA
symptoms typically last <1 to 2 hours, duration of symptoms is an unre-
liable discriminator between TIA and infarction because about 33% of
TIAs have signs of infarction on MRI.220 View a TIA as analogous to
unstable angina—that is, an ominous harbinger of a potential future
vascular event. In fact, the adjusted OR for stroke <1 month after TIA
is 30.4 (95% CI, 10.4 to 89.4),221 and the overall 90-day stroke risk after
TIA is about 9.2% to 9.5%.136-138 Some data suggest that 50% of these
subsequent events occur within 2 days after presentation to the ED.136
Published risk factors associated with increased risk for subsequent
stroke include hypertension, diabetes mellitus, symptom duration of
≥10 minutes, weakness, and speech impairment.136 A study of admitted
patients found increased risk with male sex, age ≥65 years, hyperlipid-
emia, and dysarthria.139
TIA DIAGNOSIS
The initial considerations and workup of TIA are very similar to those
of acute stroke (see earlier section “Stroke Diagnosis”), including the
emphasis on seeking mimics that can simulate TIA (Table 167-5). Pay
particular attention to performing an ECG in these patients to detect
atrial fibrillation, given its association with cardioembolic stroke and
the fact its associated stroke risk can be mitigated in many patients. An
unsettled issue in the initial workup involves brain imaging. Although a
noncontrasted CT is still the initial imaging study of choice (primarily
to rule out stroke mimics), it cannot reliably predict risk of subsequent
stroke.222 However, it has been shown that positive findings on diffusion-
weighted MRI have predictive value for subsequent early stroke risk in
TIA patients,223 as does cervical vascular imaging by magnetic reso-
nance angiography.224 Furthermore, a large meta-analysis225 of 41 studies
(n = 2541) determined that although Doppler US has test characteristics
slightly inferior to magnetic resonance angiography in detecting 70% to
99% carotid stenosis (sensitivity of 89% [95% CI, 85% to 92%] and 94%

[95% CI, 88% to 97%] and specificity of 84% [95% CI, 77% to 89%] and
93% [95% CI, 89% to 96%], respectively),225 Doppler US still performs
well enough (negative likelihood ratio of 0.13, compared to 0.06 for
MRA)225 to be useful in helping to risk-stratify TIA patients in the ED.226
Due to its relatively low specificity (84%), confirm any positive Dop-
pler US findings with magnetic resonance angiography or CT angiog-
raphy. As a screening test, CT angiography lagged behind the other two
modalities in detecting extracerebral carotid stenosis in TIA patients
(sensitivity 77% [95% CI, 68% to 84%], specificity 95% [95% CI, 91%
to 97%], negative likelihood ratio 0.24),225 despite its utility in detect-
ing intracranial vascular lesions.227 Based on these and similar data, in
2016, the American College of Emergency Physicians recommended226
that suspected TIA patients should receive a noncontrasted head CT in
the ED, and when feasible, physicians should obtain diffusion-weighted
MRI and cervical vascular imaging. These recommendations reference
a growing trend to attempt to use clinical characteristics plus imaging
to selectively manage some TIA patients as outpatients (see later section
“TIA Risk Stratification and Disposition”).
TIA TREATMENT
Treatment of TIA primarily focuses on prevention of subsequent stroke.
! ANTIPLATELET AGENTS
After TIA, the use of aspirin to prevent future vascular events is histori-
cally well accepted. Current practice includes dipyridamole plus aspirin
(reasonable as a first choice), clopidogrel, and aspirin alone. The selec-
tion of a particular antiplatelet regimen is a multifactorial decision based
on comorbid conditions, bleeding risk, prior drug use, and cost.
A very large meta-analysis (>88,000 patients)228 concluded that aspi-
rin plus dipyridamole was superior to aspirin alone for prevention of
vascular events after stroke or TIA. Aspirin plus dipyridamole was asso-
ciated with more hemorrhagic events than dipyridamole (relative risk
1.83; 95% CI, 1.17 to 2.81) but was associated with fewer hemorrhagic
events than aspirin and clopidogrel (relative risk 0.38; 95% CI, 0.25 to
0.56). However, the previously mentioned CHANCE trial (n = 5170)
found that the combination of clopidogrel and aspirin was superior to
aspirin alone for reducing the risk of stroke in the first 90 days without
increasing the risk of hemorrhage.144 These positive outcomes were
found to have persisted at 1-year follow-up.145 The Platelet-Oriented
Inhibition in New TIA and Minor Ischemic Stroke trial is currently in
progress to investigate this comparison as well.229
! ANTICOAGULATION
Adjusted-dose oral anticoagulation with warfarin has been the histori-
cal therapy of choice for stroke prevention in patients with nonvalvular
atrial fibrillation and TIA; however, an assessment of warfarin antico-
agulation for stroke prevention in the United States demonstrated a
dismal rate of optimal anticoagulation control.230 This has led to mul-
tiple randomized controlled trials of novel anticoagulants, which have
been shown to have equivalent efficacy but with less risk of intracranial
hemorrhage compared to warfarin.231 The risk of recurrent stroke in
the presence of atrial fibrillation without anticoagulation is low, prob-
ably <5% over the next 48 hours; moreover, the risk of hemorrhagic
transformation of an acute stroke is also greatest in the first 48 hours.
Consequently, in the setting of acute atrial fibrillation, anticoagula-
tion therapy typically should not be started in the ED but should be
initiated in the inpatient setting.
Multiple studies have demonstrated that, although unfractionated
heparin may help prevent recurrent stoke, its potential benefits are out-
weighed by the increased risk of intracranial hemorrhage. Multiple studies
of low-molecular-weight heparin and heparinoids have found similarly
disappointing results. A Cochrane systematic review of 24 randomized
trials (23,748 patients) found no net benefit of anticoagulants in acute
stroke.232 In addition, a meta-analysis of seven trials focused specifically
on anticoagulant use in acute cardiothrombotic stroke and found no
overall benefit.233 Therefore, the use of unfractionated heparin, low-
molecular-weight heparin, or heparinoids for emergent treatment of a
CHAPTER 167: Stroke Syndromes 1135
specific stroke subtype or TIA cannot be recommended based on avail-
able evidence, even in the presence of atrial fibrillation.234
! ENDARTERECTOMY
In TIA patients with medically treated high-grade internal carotid
artery lesions, carotid endarterectomy should be performed promptly,
because surgical benefit is greatest within 2 weeks of the TIA.235
The Carotid Revascularization Endarterectomy versus Stenting Trial
(CREST)236 and the International Carotid Stenting Study (ICSS)237 sug-
gest that carotid stenting may be a viable alternative to endarterectomy,
with similar functional outcomes up to 10 years,237,238 despite a small
increase in nondisabling stroke in stented patients in the ICSS trial.237
Carotid stenting may be especially useful in patients <70 years old236 or
in patients with higher surgical risks.239 On the other hand, the evidence-
based role of emergent or urgent carotid endarterectomy/stenting in
acute stroke is still not conclusively defined.19
TIA RISK STRATIFICATION AND DISPOSITION
Because TIAs frequently precede acute strokes, much work has been
done in attempting to develop TIA risk stratification tools in an effort
to identify which low-risk patients may safely be discharged from the
ED and worked up as outpatients. The most frequently studied of these
tools is the Age, Blood pressure, Clinical characteristics, Duration,
and Diabetes (ABCD2) scoring system.240 In 2007, the ABCD2 scoring
system was developed to incorporate and replace two previous scoring
scales (California score and ABCD score).240 Johnston et al240 initially
reported 2-day risks of subsequent stroke as 1% (ABCD2 score 0 to 3),
4.1% (score 4 to 5), and 8.1% (score 6 to 7). The 7-day stroke risks were
1.2% (ABCD2 score 0 to 3), 5.9% (score 4 to 5), and 11.7% (score 6 to 7).
Despite these initial promising data, subsequent published studies
produced conflicting conclusions as to the ABCD2 score’s utility for pre-
dicting subsequent stroke after TIA.241-243 The interrater reliability and
accuracy of the ABCD2 score have been challenged, especially with non-
specialists in actual use.244-247 A large meta-analysis (>16,000 patients)248
found inadequate positive and negative likelihood ratios (1 to 2 and 0.5
to 1, respectively) to be of practical use when deciding stroke risk in a
given patient. Overall, the ABCD2 score identified high-risk patients
poorly and had only modest success in predicting low-risk patients,
and the study authors cautioned against solely relying on the ABCD2
score to risk-stratify patients.248 In an attempt to improve accuracy of
ABCD2, the presence of two or more TIA events at 7 days (ABCD3) and
diffusion-weighted MRI (ABCD3-I) have been added to the original
scoring system. One study did demonstrate the superiority of these new
scales to predict stroke.249 However, the addition of these two data points
limits the usefulness of these scales in the ED during initial presentation.
Although use of the ABCD2 score had been recommended previ-
ously by major guidelines,219 based on the most current literature, the
American College of Emergency Physicians issued an updated clinical
policy226 in 2016. This clinical policy recommends that current risk
stratification instruments such as ABCD2 should not be used to iden-
tify TIA patients who can be safely discharged home.226 Specifically,
“the ABCD2 does not sufficiently identify the short-term risk for stroke
to use alone as a risk-stratification instrument.”226
A 13-factor Canadian TIA score250 has been developed that has shown
initial promising results; however, it has yet to be validated for general use.
In light of the difficulty in precisely identifying TIA patients who are
safe to send home from the ED, some experts have recommended that
most TIA patients be hospitalized to monitor and educate them, begin
antiplatelet therapy (unless contraindicated), rapidly treat subsequent
stroke, assess stroke risk factors, implement preventive measures, and
perform endarterectomy in appropriate patients.219
However, as a result of cost resource utilization concerns, there is
great interest in developing ED-based strategies for safely managing
TIAs as outpatients as opposed to standard admission. Numerous stud-
ies have been published exploring this issue.226 Although these studies
have largely shown that the use of special ED-directed TIA protocols
results in decreased resource use with no increased risk of subsequent
stroke, most have compared admission with extensive ED observation
1136 SECTION 14: Neurology
protocols or prompt referral to dedicated TIA clinics. A representative
example is a 2007 randomized controlled trial251 (n = 151) that demon-
strated that lower-risk patients (i.e., those without the following factors:
abnormality on initial head CT, abnormal ECG, abnormal lab values,
known possible embolic source [atrial fibrillation, cardiomyopathy, or
valvulopathy], known carotid stenosis, previous large stroke, or cre-
scendo TIAs) can be safely discharged after a 12-hour ED observation
period that includes continual cardiac and serial clinical monitoring,
coupled with a thorough initial evaluation (including neurology con-
sultation, carotid imaging, and echocardiography). More recent studies
have also included diffusion-weighted MRI in their protocols.252 Many
of these studies lack sufficient controls and are relatively small, and there
is no consensus on which specific protocol or approach is optimal. In
addition, many of the proposed algorithms require resources that are not
readily available in most EDs. However, there is general support for the
use of these types of protocols by the American College of Emergency
Physicians.226 The approach to the disposition of a specific patient must
be individualized and may depend not only on medical factors, but also
the patient’s social situation, as well as the healthcare resources available
at the particular treating institution.
! SPECIAL POPULATIONS
STROKE OR TIA WITH CONCURRENT ACUTE
MYOCARDIAL INFARCTION
The co-occurrence of acute myocardial infarction and acute stroke
has implications for acute treatment in the ED, but strong evidence-
based treatment recommendations are lacking. Troponin elevation in
acute ischemic stroke is not uncommon (prevalence, 0% to 34%253), is
associated with multiple disease processes (e.g., acute coronary syn-
drome, congestive heart failure, renal failure, myopericarditis, chronic
obstructive pulmonary disease, pulmonary embolism, sepsis, atrial
fibrillation254,255), and is independently associated with worse all-cause
mortality.256 Troponin elevation in acute stroke is most probably second-
ary to acute coronary syndrome if other obvious causes are excluded,
especially if typical ECG findings for acute coronary syndrome are
present.257 Concomitant acute stroke and acute myocardial infarction
due to paradoxical embolus traversing a patent foramen ovale has been
well described in the literature.258,259 Type A aortic dissection has also
been reported to present with simultaneous stroke and myocardial
infarction.260
Simultaneous acute ischemic stroke and myocardial infarction can be
therapeutically problematic because treating one condition with a pro-
cedure may delay a time-dependent indicated procedure for the other. In
addition, there are some therapies for acute myocardial infarction (e.g.,
heparin) that are contraindicated in acute stroke. There are no published
controlled trials directly addressing these complex patients. Nonethe-
less, based on expert consensus, the 2018 AHA/ASA guidelines gave a
Class IIa (moderate) recommendation: “For patients presenting with
concurrent AIS [acute ischemic stroke] and acute MI [myocardial
infarction], treatment with IV alteplase at the dose appropriate for
cerebral ischemia, followed by percutaneous coronary angioplasty
and stenting if indicated is reasonable.”19 Regardless of the treat-
ment strategy chosen, the risks and benefits of the various therapeutic
approaches must be carefully weighed in this situation in order to pri-
oritize the various proposed interventions, depending on the clinical
condition of the patient.261 Obtain emergent neurology and cardiology
consults on these patients, but do not delay thrombolysis for stroke if
the patient qualifies.
SICKLE CELL DISEASE
Stroke afflicts both adults and children with sickle cell disease, with an
overall prevalence of 3.8%262 compared to the overall prevalence of 2.7%
(age ≥20 years) in the general population in the United States.1 Sickle
cell disease is the most common cause of ischemic stroke in children.
Patients homozygous for hemoglobin S have the highest incidence of
stroke (0.61 in 100 patient-years), but all genotypes are at increased
risk.262 The highest incidence of hemorrhagic stroke in these patients
occurs from ages 20 to 29.262
Cerebral aneurysms and arterial abnormalities also occur with
increased frequency in patients with sickle cell disease, and careful
evaluation for subarachnoid hemorrhage is mandated for patients pre-
senting with headache and neurologic findings. Initial management is
similar to that for stroke patients without sickle cell disease, but care
should also be taken to treat the underlying sickle cell disease with oxy-
gen administration, hydration, and pain control, if necessary.
The presence of sickle cell disease has not been found to significantly
affect safety or outcomes in stroke patients treated with IV thrombolysis263
and is not considered a contraindication to thrombolytic therapy in eli-
gible patients.19 Therefore, if patients with sickle cell disease otherwise
qualify, administer IV thrombolysis.
Despite a paucity of high-quality evidence, expert consensus also
recommends emergent exchange packed red blood cell transfusion in
sickle cell patients with acute ischemic stroke, with the goal of reduc-
ing hemoglobin S levels to <30%,264 along with a target goal to achieve
a total hemoglobin level of 10 grams/dL (but no higher in order to
avoid hyperviscosity).265-267 The same therapy has been recommended
in hemorrhagic stroke in order to reduce vasospasm and secondary
ischemic infarction.264 Exchange transfusion appears to reduce the inci-
dence of subsequent ischemic stroke in children compared with simple
transfusion.268 However, if exchange transfusion is not readily available,
consider a simple packed red blood cell transfusion in these patients
while preparations for exchange transfusion are being made.
Emergent consultation with a hematologist and a stroke neurologist
is in order for these patients, and admission to a comprehensive stroke
center is indicated.
YOUNG ADULTS
Strokes in young adults (age 18 to 50 years) are increasing in incidence.269,270
Possible causes include an increasing prevalence of some traditional
cardiovascular risk factors271 (e.g., hyperlipidemia,272 diabetes,273,274
obesity275), increasing rates of recreational drug use,276 and better aware-
ness and diagnosis of stroke in this age group.269,277 In this group, cervical
arterial dissection accounts for 20% of all ischemic strokes and may often
be preceded by only minor trauma. The young adult with a cardioembolic
event may have mitral valve prolapse, rheumatic heart disease, or para-
doxical embolism259 as the originating cause. Migrainous stroke (infarc-
tion associated with typical migraine attack among those with established
recurrent migraines) is also a possibility in this age group. Some members
of this population are at risk for ischemic stroke from substance abuse.
Heroin, cocaine, amphetamines, and other sympathomimetic drugs are
often implicated.276 Patients who have human immunodeficiency virus
and a recent CD4 cell count <200 cells/mm3 are also at increased risk for
ischemic stroke (rate ratio 2.5; 95% CI, 1.3 to 4.6),278 as are young adults
who survive cancer.279 Studies suggest that younger stroke victims have
more favorable morbidity and mortality rates than elders after undergo-
ing stroke treatments such as IV thrombolysis,280 thrombectomy,281 and
decompressive surgery for large middle cerebral artery strokes.282
Therefore, treat these patients aggressively.
Acknowledgments: The author gratefully acknowledges Karen Manley
for her steadfast manuscript support, as well as Amanda Augustine,
Ashley Borden, Jarrett Gardner, Ryan Jacobsen, Liliya Kraynov, Sean Mark,
and Charles Spencer for their insightful suggestions.
REFERENCES
The complete reference list is available online at www.TintinalliEM.com.