Mayo Clinic Neurology Board Review - (Section III Cerebrovascular Disorders)

Section
Cerebrovascular III
Disorders
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Mayo Clinic Neurology Board Review, edited by Kelly D. Flemming, Oxford University Press, Incorporated, 2021. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/cuhk-ebooks/detail.action?docID=6746419.
Created from cuhk-ebooks on 2023-09-02 09:11:17.
Ischemic Stroke: Common Causes and
48 Diagnosisa
KELLY D. FLEMMING, MD
Introduction Overview of Ischemic Stroke
I
schemic stroke is the fifth leading cause of death Mechanisms of Cerebral Ischemia
and a major condition feared by older adults.
Ischemic stroke has been classically defined as a fixed focal
Clinical identification of patients with cerebral
neurologic deficit attributable to an arterial or venous terri-
ischemia is important to provide appropriate, immedi-
tory and lasting longer than 24 hours. Transient ischemic
ate treatment and initiate stroke preventive strategies.
attack (TIA) has been classically defined as a transient focal
This chapter presents an overview of the more common
neurologic deficit attributable to an arterial territory lasting
causes and mechanisms of stroke. Uncommon causes of
less than 24 hours. However, diffusion-weighted magnetic
stroke and stroke in specific situations are covered in
resonance imaging (DWI) has shown that many TIAs are
Chapter 49 (“Ischemic Stroke: Uncommon and Special
associated with tissue damage. Therefore, a tissue- based
Situations”).
diagnosis of stroke and TIA has been proposed. The pro-
posed definition of TIA is a transient episode of neurologic
dysfunction caused by focal brain, spinal cord, or retinal
Clinical Ischemic Stroke Syndromes ischemia without acute infarction. A patient who has symp-
Basic anatomy and physiology are reviewed in Section I toms lasting less than 24 hours but who has an abnormality
(“Neuroscience and Neuroanatomy”) and its Chapter 1 on DWI would be considered to have had an ischemic
(“Cerebrovascular Anatomy and Pathophysiology”). stroke.
Large-
artery clinical syndromes are summarized in Cerebral ischemia may result from several mechanisms,
including hypoperfusion, thrombosis, and embolism.
Table 48.1. Vascular brainstem syndromes are described

in Table 48.2 and illustrated in Figure 48.1. More than Hypoperfusion may cause either global deficits or focal
20 lacunar syndromes have been described; the most deficits. Watershed or border zone infarctions often result
common clinical lacunar syndromes are listed in from hypoperfusion, often in the clinical setting of an arte-
Table 48.3. rial stenosis. Thrombosis often occurs at the site of a vessel
stenosis or plaque rupture. Embolism may result from a
a
Mayo Clinic does not endorse specific products or services included in this chapter.
Abbreviations: ADC, apparent diffusion coefficient; CHADS2, congestive heart failure, hypertension, age 75 years or older, diabetes mel-
litus, and prior stroke or transient ischemic attack; CHA2DS2-VASc, congestive heart failure, hypertension, age 65 to 74 years, age 75 years
or older, diabetes mellitus, prior stroke or transient ischemic attack, female sex, and vascular disease; CT, computed tomography; CTA,
computed tomographic angiography; DWI, diffusion-weighted imaging; FLAIR, fluid-attenuated inversion recovery; MRA, magnetic res-
onance angiography; MRI, magnetic resonance imaging; PFO, patent foramen ovale; SAMMPRIS, Stenting and Aggressive Medical
Management for Preventing Recurrent Stroke in Intracranial Stenosis; TIA, transient ischemic attack
383
384 Section III. Cerebrovascular Disorders
Table 48.1 • Large-Vessel Clinical Syndromes

Vessel Clinical Presentation
Internal carotid artery Ipsilateral retinal ischemia (amaurosis)

Sensorimotor dysfunction similar to involvement of middle and anterior cerebral
artery territories
Middle cerebral artery, M1 segment Contralateral facial and arm weakness more than leg weakness
Aphasia (dominant hemisphere)
Contralateral sensory loss
Cortical sensory loss (nondominant hemisphere)
Contralateral visual field defect
Gaze deviation ipsilateral to lesion
Middle cerebral artery, anterior division Contralateral facial and arm weakness more than leg weakness
Broca aphasia (dominant hemisphere)
Middle cerebral artery, posterior division Contralateral sensory loss
Wernicke aphasia (dominant hemisphere)
Gerstmann syndrome (dominant hemisphere)
Cortical sensory loss or neglect (nondominant hemisphere)
Contralateral visual field defect
Anterior cerebral artery Contralateral leg weakness
Contralateral leg sensory loss
Apraxia
Abulia (bilateral)
Anterior choroidal artery Contralateral homonymous hemianopia (lateral geniculate body)
Contralateral facial, arm, and leg weakness (posterior limb internal capsule)
Contralateral facial, arm, and leg sensory loss (thalamus)
Posterior cerebral artery, precommunicating Contralateral sensory loss (thalamus)
part Cognitive dysfunction (thalamus)
Thalamic aphasia (rarely)
Visual dysfunction as for the postcommunicating segment
Posterior cerebral artery, postcommunicating Contralateral homonymous hemianopia
part Visual agnosias
Posterior inferior cerebellar artery Horner syndrome
Ipsilateral hemiataxia
Ipsilateral palatal weakness
Hoarse voice
Decreased pain and temperature on ipsilateral portion of face and contralateral limbs
Anterior inferior cerebellar artery Ipsilateral deafness
Ipsilateral facial weakness (lower motor neuron)
Ipsilateral hemiataxia
Contralateral sensory loss in limbs
Superior cerebellar artery Ipsilateral ataxia

Decreased sensation contralaterally
Diplopia
Basilar perforators, median and paramedian Contralateral limb weakness if unilateral; quadriparesis if bilateral
pontine perforators Possible hemiataxia (crossing pontocerebellar fibers)
CN VI and VII (affecting nuclei or nerve fibers) palsies
Internuclear ophthalmoplegia
Midbrain basilar, posterior cerebral artery Ipsilateral nuclear or fascicular CN III palsy
perforators Contralateral facial, arm, and leg weakness (corticospinal tracts)
Possible rubral tremor (red nucleus)
Possible ataxia (decussation of superior cerebellar peduncle)
Anterior spinal and vertebral perforators to Ipsilateral tongue weakness (CN XII nucleus or nerve fibers)
median and paramedian medulla Reduced contralateral arm and leg vibration sensation and proprioception (medial
lemniscus)
Contralateral arm and leg weakness (medullary pyramids)
Abbreviation: CN, cranial nerve.
Modified from Flemming KD. Cerebrovascular disease. In: Mowzoon N, Flemming KD, editors. Neurology board review: an illustrated study guide.
Rochester (MN): Mayo Clinic Scientific Press and Florence (KY): Informa Healthcare USA; c2007. p. 435-84; used with permission of Mayo
Foundation for Medical Education and Research.
Chapter 48. Ischemic Stroke: Common Causes and Diagnosis 385
Table 48.2 • Brainstem Clinical Syndromes

Name Corresponding Localization Vascular Supply Clinical Symptoms (Anatomy)
Illustration
Midbrain syndromes
Weber Figure 48.1A Medial midbrain PCA perforators Contralateral hemiparesis (cerebral peduncle)
Ipsilateral CN III palsy (CN III fascicles)
Impaired ipsilateral pupillary reflex (CN III)
and dilated pupil
Benedikt Figure 48.1B Midbrain tegmentum PCA perforators Ipsilateral CN III palsy, usually with dilated
pupil (CN III fascicles)
Contralateral involuntary movements (red
nucleus, subthalamic nucleus)
Claude Figure 48.1C Midbrain tegmentum PCA perforators Ipsilateral CN III palsy (CN III fascicles)
(dorsal) Contralateral hemiataxia and dysmetria
(dentatothalamic fibers within the superior
cerebellar peduncle)
Contralateral tremor (red nucleus)
Nothnagel Figure 48.1D Midbrain PCA perforators Ipsilateral CN III palsy (CN III fascicles)
Contralateral hemiataxia (dentatothalamic
fibers in superior cerebellar peduncle)
Pontine syndromes
Millard-Gubler Figure 48.1E Ventral pons Basilar artery Ipsilateral lower motor neuron facial paralysis
perforators, (CN VII)
median and Ipsilateral abducens paralysis (CN VI fibers)
paramedian Contralateral hemiparesis (corticospinal tract
perforators in basis pontis)
Foville Figure 48.1F Dorsal pons Basilar artery Ipsilateral lower motor neuron facial paralysis
tegmentum perforators (nucleus or fascicles of CN VII)
Ipsilateral gaze paralysis (nucleus
abducens palsy)
Contralateral hemiparesis (corticospinal tract
in basis pontis)
Ventral pontine Figure 48.1G Ventral pons Basilar artery, Ipsilateral CN VI palsy (CN VI fascicles)
paramedian Contralateral hemiparesis (corticospinal tract
perforators in basis pontis)
Marie-Foix Figure 48.1H Base of pons Basilar artery Ipsilateral cerebellar ataxia
perforators (corticopontocerebellar fibers)
Contralateral hemiparesis (corticospinal tract
in basis pontis)
Variable contralateral decrease in pain and
temperature sensation (spinothalamic tract
involvement)
Medullary syndromes
Wallenberg Figure 48.1I Lateral medulla PICA Ipsilateral hemiataxia (inferior cerebellar
peduncle)
Dysphagia, hoarseness, ipsilateral palatal
weakness (nucleus ambiguus)
Horner syndrome (sympathetic)
Decrease in pain and temperature sensation
(spinal tract and nucleus of CN V and
lateral spinothalamic tract) on ipsilateral
portion of face, contralateral portion
of body
Dejerine (medial Figure 48.1J Medial medulla Vertebral artery Contralateral hemiparesis (medullary pyramid)
medullary) perforators, Contralateral decrease in vibration or
anterior spinal proprioception sensation in limbs (medial
artery lemniscus)
Ipsilateral CN XII palsy
Abbreviations: CN, cranial nerve; PCA, posterior cerebral artery; PICA, posterior inferior cerebellar artery.
Modified from Flemming KD. Disorders of the cranial nerves. In: Mowzoon N, Flemming KD, editors. Neurology board review: an illustrated study guide.
Rochester (MN): Mayo Clinic Scientific Press and Florence (KY): Informa Healthcare USA; c2007. p. 127-62; used with permission of Mayo
A B arteries); large-
vessel intracranial disease (intracranial
internal carotid, middle cerebral, anterior cerebral, verte-
brobasilar, and posterior cerebral arteries); small- vessel
disease; abnormalities intrinsic to the blood (eg, prothrom-
botic disorders); and other diseases. Despite patients
undergoing thorough evaluations, the cause of 20% to 30%
of ischemic stroke is cryptogenic (ie, without a defined
C D cause). Cryptogenic stroke has been hypothesized to be
due to nonstenotic plaque rupture, paroxysmal atrial fibril-
lation, underlying malignancies, or undefined coagulation
disorders. Embolic stroke of undetermined source, a subset
of cryptogenic stroke, has a defined minimum evaluation
required before one concludes there is not an identifiable
cause (Box 48.1). Venous infarction is also important, and
E F
further details of venous thrombosis are provided in
Chapter 49 (“Ischemic Stroke: Uncommon and Special
Situations”).
An extensive differential diagnosis of cerebral ischemia
based on these broad categories is listed in Box 48.2.
Cardioembolic disease is most prevalent (30%-40%), fol-
G lowed by lacunar disease (20%-30%), cryptogenic disease
(20%-30%), large-vessel disease (10%-15%), and coagula-
H tion disorders (<5%).
It is important to keep in mind that certain conditions
may mimic cerebral ischemia (Box 48.3).
• The proposed definition of TIA is a transient episode
of neurologic dysfunction caused by focal brain, spinal
I J cord, or retinal ischemia without acute infarction. A
patient who has symptoms lasting <24 hours but who
has an abnormality on DWI would be considered to
have had an ischemic stroke.
• Common mimics of TIA include focal seizures,
migraine equivalents, and metabolic disorders.
• The most prevalent etiologic factor of stroke is
Figure 48.1 Brainstem Clinical Syndromes. See Table 48.2
cardioembolic; however, up to 30% of strokes are
for details. A, Weber syndrome. B, Benedikt syndrome. C,
cryptogenic.
Claude syndrome. D, Nothnagel syndrome. E, Millard-
• The term embolic stroke of undetermined source helps
Gubler syndrome. F, Foville syndrome. G, Ventral pontine
further define subsets of patients with cryptogenic
syndrome. H, Marie-Foix syndrome. I, Wallenberg syndrome.
stroke and defines the minimum workup to diagnose
J, Dejerine syndrome.
this type of stroke.

(From Flemming KD. Disorders of the cranial nerves. In: Mowzoon N,
Flemming KD, editors. Neurology board review: an illustrated study
General Approach to Evaluation of a Patient
guide. Rochester [MN]: Mayo Clinic Scientific Press and Florence
With Arterial Cerebral Ischemia
[KY]: Informa Healthcare USA; c2007. p. 127- 62; used with
permission of Mayo Foundation for Medical Education and Research.) Evaluation of a patient with suspected arterial cerebral
ischemia should begin with an evaluation to identify
whether the patient is a candidate for intervention (intra-
cardiac embolus (thrombus, myxomatous emboli, or vege-
venous tissue plasminogen activator, intra-arterial throm-
tation), from artery-to-artery emboli, or, rarely, from air, fat,
bolytics, or mechanical thrombectomy). This evaluation is
or amniotic fluid.
covered in detail in Chapter 50 (“Acute Ischemic Stroke
Evaluation and Treatment”). The National Institutes of
Causes of Cerebral Ischemia Health Stroke Scale score (often calculated at hospital
Causes of arterial cerebral ischemia can be classified admission) helps determine the risk of hemorrhage with
broadly into 6 categories: cardioembolic disease; large- intravenous tissue plasminogen activator therapy and pre-
vessel extracranial disease (aorta, carotid, and vertebral dicts the outcome after cerebral ischemia.
Table 48.3 • Lacunar Syndromes

Syndrome Typical Clinical Presentation Typical Localization
Pure motor hemiparesis Contralateral facial, arm, leg weakness Internal capsule
Corona radiata
Pure sensory stroke Contralateral facial, arm, leg sensory loss Thalamus (ventral posterolateral and
posteromedial nuclei)
Sensorimotor stroke Contralateral facial, arm, leg weakness Thalamocapsular
Contralateral facial, arm, leg sensory loss
Ataxic hemiparesis Hemiataxia and hemiparesis on same side Basis pontis
of body Thalamocapsular
Corona radiata
Clumsy hand dysarthria Facial weakness Basis pontis
Dysarthria
Slight hemiparesis
Cerebellar dysmetria
From Flemming KD. Cerebrovascular disease. In: Mowzoon N, Flemming KD, editors. Neurology board review: an illustrated study guide. Rochester
(MN): Mayo Clinic Scientific Press and Florence (KY): Informa Healthcare USA; c2007. p. 435-84; used with permission of Mayo Foundation for
Medical Education and Research.
modifiable risk factors, 3) monitor for stroke-related compli-

Box 48.1 • Embolic Stroke of Undetermined Source cations, and 4) initiate rehabilitation. The diagnostic
workup is aimed at identification of the potential cause of
Criteria for diagnosis of embolic stroke of
undetermined source
cerebral ischemia. Hence, the appropriate antithrombotic
(antiplatelet agent vs anticoagulant) for secondary preven-
Stroke detected with CT or MRI that is not lacunar
tion can be selected. In addition, identification of the
Absence of extracranial or intracranial
atherosclerosis causing ≥50% luminal stenosis in cause— for example, a symptomatic high- grade carotid
arteries supplying the area of ischemia stenosis— may identify patients who require surgical or
No major-risk cardioembolic source of embolism endovascular treatment. The second goal prompts modifica-
No other specific cause of stroke identified (eg, arteritis, tion of the contributing risk factors. The third goal is to
dissection, migraine/vasospasm, drug misuse) identify and prevent complications related to cerebral isch-
Proposed diagnostic assessment for embolic stroke of emia (aspiration pneumonia, urinary tract infections, deep
undetermined source vein thrombosis or pulmonary embolism, myocardial
Brain CT or MRI infarction, arrhythmias, and depression). Rehabilitation
12-lead ECG also is an important aspect of treatment (see Chapter 54,
Precordial echocardiography “Neurorehabilitation”).
Cardiac monitoring for ≥24 h with automated A general approach to stroke evaluation (Figure 48.2) is
rhythm detection based on the pretest probability (ie, prevalence) of causes
in addition to the identification of causes that change man-
Imaging of the extracranial and intracranial arteries

supplying the area of brain ischemia (catheter, agement. The approach varies depending on other factors
MR, or CT angiography or cervical duplex plus that influence the pretest probability of individual causes
transcranial Doppler ultrasonography)
collected in the initial history, physical examination, labo-
Abbreviations: CT, computed tomography; ECG, ratory studies, and imaging (Box 48.4). Additional recom-
electrocardiography; MR, magnetic resonance; MRI, mendations for diagnostic evaluation are noted in
magnetic resonance imaging.
individual sections below.
From Hart RG, Diener HC, Connolly SJ. Embolic strokes of
undetermined source: support for a new clinical construct:
Computed tomography (CT) and magnetic resonance
authors’ reply. Lancet Neurol. 2014 Oct;13(10):967; used imaging (MRI) are common tools used in the evaluation of
with permission. cerebral ischemia. CT of the head should be performed for
all patients who present with suspected stroke. This CT
aids in the distinction between hemorrhage and ischemia.
After acute decisions are made, the patient is often hos- Although it may be negative for stroke in the first 24 hours,
pitalized. Thereafter, goals include 1) identify the cause of the early signs of ischemia include sulcal effacement, loss
cerebral ischemia and select the appropriate antithrombotic of the gray-white junction, and a hyperdense artery (eg,
(antiplatelet agent vs anticoagulant), 2) identify and treat basilar or middle cerebral artery).
The most useful brain MRI sequences for cerebral isch- years, hypertension, diabetes mellitus, history of thrombo-
emia are fluid- attenuated inversion recovery (FLAIR), embolism, and congestive heart failure. The CHADS2 (con-
DWI, and the apparent diffusion coefficient (ADC) map gestive heart failure, hypertension, age ≥75 years, diabetes
(Figure 48.3). DWI measures the random diffusion of water mellitus, and prior stroke or TIA) score (Table 48.4) and
molecules. Random diffusion of water is relatively free in the CHA2DS2- VASc (congestive heart failure, hyperten-
the extracellular space and more restricted in the intracel- sion, age 65- 74 years, age ≥75 years, diabetes mellitus,
lular space. When cytotoxic edema forms early in cerebral prior stroke or TIA, female sex, and vascular disease) score
ischemia, water shifts from the extracellular space to the can be used to predict the risk of recurrent thromboembo-
intracellular space, and diffusion is restricted. In general, lism (Table 48.5). The risk may be as high as 10% to 12%
the DWI signal is bright and the ADC map is dark in acute per year for patients with multiple risk factors.
cerebral ischemia. These sequences both normalize over 2 Paroxysmal atrial fibrillation can be missed with 24-
to 3 weeks; thus, DWI is useful in determining the lesion hour telemetry or Holter monitoring. Up to 15% of patients
acuity, confirming clinical localization, and confirming the with cryptogenic stroke may have paroxysmal atrial fibril-
diagnosis and tissue damage. The DWI signal must be eval- lation as a cause of their stroke. Extended cardiac monitor-
uated with the ADC map and the clinical history, since a ing (surface monitoring or implantable device) for at least
DWI signal abnormality can also be present with acute 30 days should be considered for patients with crypto-
demyelinating lesions, neoplasms, infection, Creutzfeldt- genic stroke. Ongoing research is evaluating echocardio-
Jakob disease, and other disease processes. graphic, serum, and electrocardiographic biomarkers that
would predict atrial fibrillation or atrial cardiopathy with-
out extended monitoring.
Warfarin (international normalized ratio goal, 2-3) is
Ischemic Stroke by Etiologic Factor superior to aspirin and superior to clopidogrel plus aspirin
for prevention of thromboembolism due to atrial fibrilla-
Cardioembolic Source
tion. Four novel anticoagulants— dabigatran (a direct
Approximately 30% to 40% of ischemic strokes or TIAs thrombin inhibitor), rivaroxaban, apixaban, and edoxaban
are due to a cardioembolic source; thus, the pretest proba- (factor Xa inhibitors)—have been compared with warfarin
bility for any patient is high. Major cardioembolic sources and are alternatives to warfarin for nonvalvular atrial
are those for which the medical literature clearly shows a fibrillation. (See also Chapter 51, “Secondary Prevention
causal relationship with cerebral ischemia and for which of Ischemic Stroke.”) The Watchman Left Atrial Appendage
clinical trials of treatment exist (Box 48.5). Minor cardio- Closure Device (Boston Scientific Corp), is an alternative
embolic sources are those for which the medical literature to long-term anticoagulation for patients with atrial fibril-
presents controversial or inconclusive findings related to lation who are at high risk for intracranial or systemic
the relationship to cerebral ischemia. bleeding when receiving anticoagulation. The Watchman
Cardiac examination, chest radiography, and electrocar- occludes the left atrial appendage and thus prevents stroke.
diography are recommended for all patients with cerebral
ischemia. Selected patients may benefit from echocardiog- Myocardial Infarction
raphy, extended cardiac monitoring (Holter, event recorder, Stroke in the presence of myocardial infarction is more
mobile cardiac outpatient telemetry, or insertable cardiac common for patients who have 1 or more of the following
monitoring device), or blood cultures. Suspicions of car- risk factors: older age, apical or anterior wall myocardial
diac disease that would warrant such tests include multi- infarction, left ventricular dysfunction or atrial fibrillation,
ple arterial territory ischemic strokes, no evidence of mural thrombi or severe wall motion abnormality seen on
large-or small-vessel disease as a cause, palpitations, large echocardiography, prior history of stroke, hypertension, or
left atrium, mitral valve disease, obstructive sleep apnea, history of systemic or pulmonary embolism. The stroke
and history of cardiac disease. Cardiac CT and MRI are risk is highest in the first week after myocardial infarction,
evolving and may be alternative tests to echocardiography. but the increased risk persists for up to 6 months. Short-
term anticoagulation in addition to aspirin may be recom-
Atrial Fibrillation mended for high-risk patients with a recent myocardial
Nonvalvular atrial fibrillation is one of the most common infarction.
causes of cerebral ischemia. Atrial fibrillation affects 1% of
the general US population but 10% of persons older than Endocarditis
75 years. Both paroxysmal fibrillation and chronic atrial Infectious endocarditis and nonbacterial thrombotic endo-
fibrillation are risk factors for ischemia, but paroxysmal carditis are uncommon causes of cerebral ischemia.
atrial fibrillation is often difficult to prove. Infectious endocarditis often occurs with intravenous drug
Factors that increase the risk of thromboembolism in abuse (generally involving the right- sided heart valves)
the presence of atrial fibrillation include age older than 75 and for patients with prosthetic valves or structural heart
valve disease. Staphylococcus aureus and the viridans Although not technically a cardiac source, pulmonary
streptococci group are the most typical sources. Neurologic shunts are often discovered on echocardiography and
complications of infectious endocarditis include cerebral thus are discussed herein. Pulmonary shunts are most
ischemia, mycotic aneurysms, and intracranial abscesses. commonly seen in Osler- Weber-
Rendu disease. Also
Other clinical clues to the diagnosis may include a new known as hereditary hemorrhagic telangiectasia, this is
heart murmur, fever, Janeway lesions, Osler nodes, and an autosomal dominant condition characterized by telan-
Roth spots. Diagnosis is typically made with blood cul- giectasias in multiple organs. Patients also may have vas-
tures and echocardiography. Treatment is to identify the cular malformations of the brain, but more commonly,
source of the endocarditis and then treat with appropriate they are evaluated for cerebral ischemia relevant to pul-
antibiotics. Surgery may be necessary for ruptured or monary fistulae. Treatment is embolization of the fistulae.
enlarging mycotic aneurysms. Antithrombotic agents are generally contraindicated
Nonbacterial thrombotic endocarditis may be associ- because of the high risk of bleeding from nasal and gastro-
ated with systemic lupus erythematosus (Libman- Sacks intestinal tract telangiectasias.
endocarditis) or malignancy (marantic endocarditis). In
both these forms of endocarditis, the valvular vegetations • The CHADS2 score and the CHA2DS2-VASc score can be
consist of immune complexes, white blood cells, fibrin used to predict the risk of recurrent thromboembolism
and platelet thrombi, and fibrosis. Mitral, aortic, and tri- for patients with atrial fibrillation.
cuspid valves are commonly involved in Libman-Sacks • Extended cardiac monitoring (≥30 days) should be
endocarditis, and the mitral and aortic valves are involved considered for patients with cryptogenic stroke.
with malignancies. In addition to malignancies and sys-
temic lupus erythematosus, HIV infection and antiphos-
Extracranial Large-Vessel Disease
pholipid antibody syndrome can be associated with
nonbacterial thrombotic endocarditis. The diagnosis is Approximately 15% to 20% of strokes are due to large-
made with echocardiography. Blood cultures are used to vessel extracranial disease, with the majority of these
rule out infection, and systemic laboratory tests are per- (10%-12% of strokes) due to carotid atherosclerosis.
formed to identify contributing causes. Treatment often All patients with cerebral ischemia relevant to the
involves surgery or valvuloplasty if the heart valve has anterior circulation should have extracranial carotid
been damaged and anticoagulation for selected patients. imaging. Magnetic resonance angiography (MRA), CT
angiography (CTA), or carotid ultrasonography could be
Valvular Heart Disease performed. Compared with carotid ultrasonography, MRA
Valvular heart disease and mechanical heart valves and CTA are superior in sensitivity and specificity for
increase the risk of stroke. The thromboembolic risk high-grade internal carotid artery stenosis (Figure 48.4).
increases with multiple mechanical valves, associated left Yet, they may be less available and more costly, and they
ventricular dysfunction, associated atrial fibrillation, asso- generally require use of a contrast agent. CTA of the neck
ciated left atrial thrombus, advanced age, previous throm- is useful for reviewing the anatomy of the bifurcation in
boembolic event, mitral position of the valve, and certain relation to the cervical spine; however, if the plaque is
types of mechanical valves. Anticoagulation with warfarin heavily calcified, the degree of stenosis may be difficult to
is preferred over antiplatelet agents, and the level of anti- discern. The usefulness of carotid ultrasonography is lim-
coagulation depends on the type and position of the ited for diagnosing arterial dissection, which generally
mechanical valve. occurs distally toward the skull base. CTA or MRA should
be considered for patients in whom arterial dissection is a
Patent Foramen Ovale suspicion. Magnetic resonance plaque imaging may aid in
The discovery of a patent foramen ovale (PFO) in the eval- determining if there is a vulnerable plaque.
uation for causes of stroke presents considerable contro- In the patient with posterior circulation symptoms, ver-
versy. Approximately 25% of the general population have tebrobasilar imaging may be performed with either MRA
a PFO. Some epidemiologic studies suggest a relationship or CTA.
to cerebral ischemia, and other studies refute the concept. It is now common in clinical practice that a CTA of the
Purported risk factors thought to increase the probability head and neck is performed in the emergency setting for
that a PFO has a relationship to cerebral ischemia include acute stroke.
size, shunting characteristics (right to left), associated
atrial septal aneurysm, known deep vein thrombosis, and Aortic Disease
cortical stroke. PFO closure is considered in patients with The aorta may be a source of stroke when severe athero-
high-risk features and no other identified cause. Treatment sclerosis is present or there is an associated dissection.
is less clear for patients who do not fit these high-risk cri- Epidemiologic studies have produced conflicting data on
teria, but antiplatelet agents are commonly used. the relationship of severe (>4 mm) aortic plaque and
Box 48.2 • Differential Diagnosis of Ischemic Stroke
Cardiac disorder Radiation induced

Atrial fibrillation Eales disease
Mitral stenosis Arterial dolichoectasia
Left ventricular thrombus Endovascular lymphoma
Atrial myoma Thrombosed aneurysm with emboli
Dilated cardiomyopathy
Anterior wall myocardial infarction Small-vessel disease
Prosthetic valves Lipohyalinosis or atherosclerosis
Endocarditis (eg, bacterial, nonbacterial, marantic) Vasculitis
Patent foramen ovale Varicella zoster vasculitis
Atrial septal aneurysm Cryoglobulin-related angiitis
Mitral valve calcification Angiitis related to lymphomatoid malignancies
Fibroelastoma Henoch-Schönlein purpura
Pulmonary fistula (Osler-Weber-Rendu disease) Hematologic and coagulation disorders
Air or fat emboli (rare)
Disorders of coagulation factors
Large-vessel extracranial disorder Protein C or protein S deficiency
Atherosclerosis Antithrombin III deficiency
Dissection Activated protein C resistance or factor V Leiden
mutation
Radiation vasculopathy
Prothrombin 20210 mutation
Fibromuscular dysplasia
Disorders of red blood cells
Vasculitis
Sickle cell anemia
Takayasu vasculitis
Polycythemia (primary or secondary)
Giant cell arteritis
Paroxysmal nocturnal hemoglobinuria
Large-vessel intracranial disorder Disorders of white blood cells
Atherosclerosis Lymphoma
Dissection Leukemia
Inflammatory vasculitis Disorders of platelets
Isolated CNS angiitis Disseminated intravascular coagulation
Necrotizing vasculitides (eg, granulomatosis with Thrombotic thrombocytopenic purpura
polyangiitis [Wegener granulomatosis], polyarteritis Idiopathic thrombocytopenic purpura
nodosa, eosinophilic granulomatosis with Essential thrombocythemia
polyangiitis [Churg-Strauss syndrome],
Thrombocytosis
lymphomatoid granulomatosis)
Paraproteinemia
Hypersensitivity angiitis with connective tissue disease
(eg, sarcoidosis, systemic lupus erythematosus, Uremia
Sjögren syndrome, rheumatoid arthritis) Disorders of plasma cells
Susac syndrome (retinocochleocerebral arteriopathy) Myeloma
Kohlmeier-Degos disease Cryoglobulinemia
Behçet syndrome Other

Infectious vasculitis Antiphospholipid antibody syndrome
Varicella-zoster virus Hyperhomocystinemia
HIV Malignancy-associated coagulopathy
Hepatitis B and hepatitis C viruses
Epstein-Barr virus Other
Cytomegalovirus CADASIL
Noninflammatory vasculopathies Sneddon syndrome
Moyamoya disease Fabry disease
Drug induced (eg, cocaine, methamphetamine, MELAS
phenylpropanolamine, ergotamines) Homocystinuria
Postpartum cerebral angiopathy Organic acidemias
Abbreviations: CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CNS, central
nervous system; MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes.
Modified from Flemming KD. Cerebrovascular disease. In: Mowzoon N, Flemming KD, editors. Neurology board review: an illustrated
study guide. Rochester (MN): Mayo Clinic Scientific Press and Florence (KY): Informa Healthcare USA; c2007. p. 435-84; used with
permission of Mayo Foundation for Medical Education and Research.
Box 48.3 • Mimics of Cerebral Ischemia
Differential diagnosis of transient neurologic Differential diagnosis of acute fixed focal neurologic deficit
deficits Ischemic stroke
Transient ischemic attack Cerebral hemorrhage
Seizure Bell palsy
Migraine Peripheral mononeuropathy
Metabolic disturbance (hypoglycemia, Encephalitis
hypocalcemia, or hypercalcemia)
SMART syndrome
Myasthenia gravis
RCVS
Paroxysmal symptoms in multiple sclerosis
PRES
RCVS
Unmasking of prior stroke due to infection or metabolic
Amyloid angiopathy–related spells derangement
Psychogenic Psychogenic
Abbreviations: PRES, posterior reversible encephalopathy syndrome; RCVS, reversible cerebrovasoconstrictive syndrome; SMART,
strokelike migraine attacks after radiotherapy.
cerebral ischemia. Treatment recommendations are also The current recommendations of the American Heart
conflicting, but currently an antiplatelet agent and a statin Association are as follows: For patients with recent cere-
are commonly used. bral ischemia (within the past 6 months) due to ipsilateral
Clues to a stroke due to aortic dissection may include stenosis of 70% to 99%, carotid endarterectomy is recom-
associated chest or back pain, an aortic regurgitation mur- mended if the perioperative morbidity rate is less than 6%.
mur, hypotension, reduced peripheral pulses, and a differ- Selected patients with moderate-grade stenosis could be
ence in blood pressure between the 2 arms. Diagnosis of a considered for carotid endarterectomy if perioperative
stroke is suggested by a widened mediastinum on chest morbidity and mortality rate is less than 6%. Carotid
radiography, but if suspicion is high, CT of the chest or angioplasty and stenting could be considered as an alter-
transesophageal echocardiography can be performed to native to carotid endarterectomy for symptomatic patients
confirm the diagnosis. Management of aortic dissection with an average or low risk of complications if the stenosis
complicated by cerebral ischemia is controversial. The is more than 50% by conventional angiography or more
prognosis is often poor with either medical or surgical than 70% by noninvasive imaging. For patients with
management. symptomatic carotid artery occlusion, medical manage-
ment is superior to surgical considerations such as super-
Carotid Atherosclerosis ficial temporal artery– to–
middle cerebral artery bypass.
Carotid atherosclerosis at the bifurcation accounts for 10% After carotid intervention, antiplatelet therapy and risk
to 12% of ischemic strokes and is more common than factor management are recommended (eg, moderate-to
intracranial stenosis. Clinical syndromes associated with high-intensity statin treatment, blood pressure goal <130/
carotid stenosis are discussed at the beginning of this chap- 80 mm Hg, normoglycemia, smoking cessation).
ter. The treatment of asymptomatic carotid stenosis is dis-
cussed in Chapter 51 (“Secondary Prevention of Ischemic Extracranial Artery Dissection
Stroke”). It is important to distinguish symptomatic from Extracranial dissection can affect either the internal carotid
asymptomatic carotid stenosis since the treatment differs arteries or the vertebral arteries. This is a common cause of
substantially. Symptomatic refers to a cerebral infarction stroke for patients younger than 45 years (causing 2% of
or TIA in the anterior circulation ipsilateral to the athero- strokes in the general population but 10%-25% of strokes
matous diseased internal carotid artery. in the young). About 50% of dissections result from identi-
The treatment of symptomatic carotid stenosis has fiable trauma, and 50% occur without an identifiable pre-
evolved over time, guided originally by the North American disposing event. Conditions that may predispose to
Symptomatic Carotid Endarterectomy Trial (NASCET), the dissection include fibromuscular dysplasia, the vascular
Carotid Revascularization Endarterectomy vs Stenting type of Ehlers-Danlos syndrome (formerly type IV), Marfan
Trial (CREST), and the International Carotid Stenting syndrome, polycystic kidney disease, pseudoxanthoma
Study (ICSS). elasticum, and osteogenesis imperfecta.
Suspected cerebral ischemia
Emergency department evaluation

• Head CT
• Head/neck CT angiography (NIHSS ≥6)
• ECG
• Tests: glucose, INR, PTT, troponin
Consider brain MRI

(especially if cause or location is in question or to assess topography such as
small-vessel disease; low yield if visible on CT and mechanism already known)
Anterior circulation Posterior circulation
Extracranial carotid studya

(if not already done)
Atrial fibrillation ACd (Watchman)
Extracranial internal
Internal carotid
carotid artery Lacunar AP
artery dissection
atherosclerotic stenosis
Nonlacunar syndrome
Additional tests
100% 70%-99%b 50%-69% <50% depending on
pretest probabilityg
AP (vs AC) AP CEA/CAS For selected Abnormal CXR or High suspicion

AP patients, consider ECG or suspicion of cardioembolic
advanced of cardioembolic source
plaque imagingc source
(−)
AP TTEe TEEf
(+) (−)
Treat Prolonged cardiac

appropriately monitoring
Figure 48.2 General Approach to Evaluation of Cerebral Ischemia. Factors that influence the pretest probability of individual
causes of stroke are listed in Box 48.3. Watchman Left Atrial Appendage Closure Device (Boston Scientific Corp) is an atrial
appendage closure device. AC indicates anticoagulation; AP, antiplatelet agent; CAS, carotid angioplasty and stenting;
CEA, carotid endarterectomy; CT, computed tomography; CXR, chest radiograph; ECG, electrocardiography; INR,
international normalized ratio; MRI, magnetic resonance imaging; NIHSS, National Institutes of Health Stroke Scale; PTT,
partial thromboplastin time; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography.

a
The type of study should be considered on the basis of anticipated cause. For example, if one is assessing for carotid atherosclerosis,
ultrasonography may be least expensive, although the sensitivity and specificity are inferior to CT or magnetic resonance (MR)
angiography. Whereas if one is assessing for suspected dissection, CT or MR angiography would be preferred.
b
Of stroke evaluations, either 70% to 99% are with noninvasive imaging or more than 50% are with invasive imaging.
c
For patients with recurrent cerebral ischemia in the same vascular distribution, without a more readily identifiable cause (ie, cardiac or
small-vessel disease), carotid plaque imaging may identify a ruptured plaque or ulceration, or both.
d
Warfarin is preferred in valvular atrial fibrillation. Thus, if the evaluation is for new-onset atrial fibrillation, TTE may be warranted to
assess the valves. Warfarin or direct oral anticoagulant is considered for nonvalvular atrial fibrillation. A Watchman device may be
considered for patients with high bleeding risk on anticoagulation.
e
TTE may be superior to TEE in detection of left ventricular thrombi. A bubble study should be considered to assess for patent foramen
ovale in appropriate cases.
f
TEE is superior to TTE in the assessment for patent foramen ovale, left atrium and atrial appendage characteristics, and endocarditis.
An alternative to avoid sedation might be a cardiac CT or MRI.
g
Consideration for intracranial vessel imaging, vessel wall imaging, spinal fluid, coagulation laboratory studies, autoimmune laboratory
studies, conventional angiography, malignancy screening, and other tests depends on the suspicion for specific causes and whether such
tests would change management (see text). In general, patients younger than 45 years require more extensive evaluation.
The intimal tear results in a false lumen, and occasionally

Box 48.4 • Factors That Increase the Pretest there is an associated pseudoaneurysm.
Probability of Individual Stroke Mechanisms Clinically, patients may have anterolateral cervical and
retro-orbital pain with carotid dissection or posterior head
pain with vertebral dissection. A carotid dissection may be
Cardioembolic
associated with an ipsilateral Horner syndrome due to the
History of atrial fibrillation, congestive heart failure, or sympathetic nerves traveling near the carotid artery.
myocardial infarction
Typically, patients have miosis and ptosis but not anhidrosis.
Abnormal chest examination
The sympathetic fibers to the sweat glands of the face bifur-
Abnormal electrocardiogram cate from those traveling to the eye at the level of the external
Cortical stroke or multiple arterial territories carotid artery. Rarely, other cranial nerves (eg, cranial nerves
X and XII) can be affected. Patients with carotid dissection
Large-vessel extracranial have typical anterior circulation symptoms. Patients with
Atherosclerotic risk factors vertebral artery dissection commonly have Wallenberg syn-
Bruit on examination drome (also called lateral medullary syndrome).
Systemic symptoms or high sedimentation rate (giant Carotid ultrasonography has a low sensitivity for dis-
cell arteritis), or both section, especially if the vessel is nonstenotic. MRA or
History of head or neck injury (dissection) CTA is the test of choice. Conventional angiography is
reserved for patients for whom dissection is highly sus-
Large-vessel intracranial pected but noninvasive tests are unrevealing. Radiographic
findings may include a tapered, flamelike appearance; a
Atherosclerotic risk factors
double lumen; and an intimal flap.
Multiple stereotypic transient ischemic attacks
Optimal treatment for dissection is unclear. Guidelines
Systemic symptoms, seizures, young patient (age ≤45 y)
recommend either antiplatelet agents or anticoagulation
(vasculitis)
on the basis of observational studies and 1 underpowered
Illicit drug use
clinical trial. Angioplasty and stenting can be considered
if the patient has no response to medical therapy, but they
Small vessel
involve a risk of further extension of the dissection.
Atherosclerotic risk factors
Classic clinical lacunar syndrome Fibromuscular Dysplasia
Waxing and waning symptoms Fibromuscular dysplasia is a nonatherosclerotic, noninflam-
matory arteriopathy leading to arterial stenosis and occlu-
Coagulation sion and predisposing to dissection (Figure 48.6). This
Personal or family history of clotting disorder condition is more common in women and white persons. It
Multiple miscarriages affects the renal vessels most commonly (60%-75%); the
Age, race (sickle cell disease) extracranial carotid or vertebral arteries are the second most
common site (20%-30%). Intracranial vessels and the iliac,
Young age (age ≤45 y)
femoral, subclavian, and visceral arteries may also be
Multiple arterial territories
affected. Patients may be asymptomatic, have pulsatile tin-
Venous thrombosis
nitus, or present with focal cerebral ischemia. Patients may
Abbreviation: y, years. also have hypertension due to involvement of the renal
Modified from Flemming KD. Diagnosis of stroke mechanisms arteries. The diagnosis is based on the angiographic appear-
and secondary prevention. In: Barrett KM, Meschia JF, ance of a “string of beads” or “beading” (ie, alternating con-
editors. Stroke. Chichester (West Sussex): Wiley-Blackwell; stricted and dilated segments generally of the distal cervical
c2013. p. 55-77. (Neurology in Practice series); used with
permission. carotid). Conventional angiography is superior to MRA;
however, gadolinium-enhanced MRA may show changes as
well. Treatment involves antiplatelet agents and manage-
ment of concomitant hypertension if present.
Cerebral arterial dissection typically occurs at extracra-
nial sites. In the internal carotid arteries, dissection often Vasculitis
occurs 2 to 3 cm distal to the bifurcation and may have a Vasculitides affecting the large-vessel extracranial arteries
flame-like tapering on angiography (Figure 48.5). Dissection include giant cell arteritis (see Chapter 100, “Secondary
of the vertebral arteries typically occurs at C1-2, where the Headache Disorders”) and Takayasu arteritis (also called
artery courses posteriorly and enters the foramen magnum. pulseless disease).
A B
Figure 48.3 Cerebral Ischemia. A, Diffusion-weighted image shows restriction of diffusion in the distribution of the right
middle cerebral artery. B, An apparent diffusion coefficient (ADC) map shows corresponding ADC hypointensity, confirming
ischemia as the reason for the diffusion hyperintensity.
Box 48.5 • Major and Minor Cardiac Risk Sources • For the treatment of symptomatic internal carotid
stenosis, the current recommendations of the
Major risk sources Minor risk sources American Heart Association are as follows: For
patients with recent cerebral ischemia (within the past
Atrial fibrillation Mitral valve prolapse
6 months) due to ipsilateral stenosis of 70%-99%,
Mitral valve stenosis Severe mitral annular
carotid endarterectomy is recommended if the
Prosthetic calcification
perioperative morbidity rate is <6%. Selected patients
cardiac valve Patent foramen ovale
with moderate-grade stenosis could be considered for
Recent myocardial Atrial septal aneurysm
infarction carotid endarterectomy if perioperative morbidity and
Calcific aortic stenosis
mortality rates are <6%.
Left ventricular or left Left ventricular
atrial thrombus • After carotid intervention, antiplatelet therapy and risk
regional wall
Atrial myxoma motion factor management (including high-intensity statin
abnormalities therapy) are recommended.
Infectious endocarditis
Mitral valve strands • Internal carotid artery dissection is a common cause of
Dilated
cardiomyopathy stroke in young people, often associated with
ipsilateral anterolateral neck and retro-orbital pain and
Marantic endocarditis
with an ipsilateral Horner syndrome.
From Flemming KD. Cerebrovascular disease. In: Mowzoon N,
Flemming KD, editors. Neurology board review: an Intracranial Large-Vessel Disease
illustrated study guide. Rochester (MN): Mayo Clinic
Scientific Press and Florence (KY): Informa Healthcare Intracranial large-
vessel disease accounts for approxi-
USA; c2007. p. 435-84; used with permission of Mayo
mately 5% to 10% of all strokes— most commonly, the
strokes due to atherosclerosis. The differential diagnosis is
Table 48.4 • CHADS2 Score A B

Historical Feature Points
History of congestive heart failure 1

Hypertension (any history) 1
Age ≥75 y 1
Diabetes mellitus 1
Secondary prevention for patient with 2
prior cerebral ischemia or systemic
thromboembolism
Abbreviation: CHADS2, congestive heart failure, hypertension, age 75
years or older, diabetes mellitus, and prior stroke or transient
ischemic attack.
Data from Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW,
Radford MJ. Validation of clinical classification schemes for
predicting stroke: results from the National Registry of Atrial
Fibrillation. JAMA. 2001 Jun 13;285(22):286
Table 48.5 • Stroke Risk per 100 Person-years

CHADS2 Score With Warfarin Without Warfarin NNT
0 0.25 0.49 417

1 0.72 1.52 125
2 1.27 2.50 81
3 2.20 5.27 33
4 2.35 6.02 27
5 or 6 4.60 6.88 44 Figure 48.4 Magnetic Resonance Angiography of Carotid
Abbreviations: CHADS2, congestive heart failure, hypertension,
Stenosis. A, High-grade stenosis (near occlusion) (arrow) of
age 75 years or older, diabetes mellitus, and prior stroke or transient the proximal left internal carotid artery with reduced
ischemic attack; NNT, number needed to treat. caliber of the distal internal carotid artery. B, Moderately
severe stenosis (50%- 70%) in the area of the right
carotid bulb.
listed in Box 48.2. Intracranial vasculature can be visual-
(From Flemming KD. Cerebrovascular disease. In: Mowzoon N,
ized noninvasively with MRA or CTA. Conventional angi-
Flemming KD, editors. Neurology board review: an illustrated
ography is the gold standard and is reserved for patients in
study guide. Rochester [MN]: Mayo Clinic Scientific Press and
whom small-vessel vasculitides are of concern.
Florence [KY]: Informa Healthcare USA; c2007. p. 435-84; used
Intracranial atherosclerosis accounts for 5% of strokes
with permission of Mayo Foundation for Medical Education and

and is more common in African Americans and Asian
Research.)
Americans than whites. Clinical suspicion for intracranial
atherosclerosis may arise if a patient has stereotyped epi-
sodes of cerebral ischemia. The episodes may be postural,
of stroke, often perioperatively. Because of the success of
suggesting hypoperfusion, and they often have typical vas-
the SAMMPRIS medical arm, dual antiplatelet therapy is
cular risk factors. Treatment is generally an antiplatelet
often considered for up to 90 days.
agent and risk factor management, including a statin. The
American Heart Association recommends antiplatelet
Moyamoya Disease
therapy and risk factor management. The Stenting and
Aggressive Medical Management for Preventing Recurrent Moyamoya disease is a rare disorder resulting in distal
Stroke in Intracranial Stenosis (SAMMPRIS) trial com- intracranial internal carotid artery stenosis with unusual
pared patients receiving medical treatment (aspirin and collateral formation of the lenticulostriate arteries. The
clopidogrel for 90 days and risk factor management) with lenticulostriate arteries resemble puffs of smoke on con-
patients undergoing angioplasty and stenting. The group ventional angiography—hence, the term moyamoya (mean-
that underwent angioplasty and stenting had a higher rate ing foggy or smoky in Japanese) (Figure 48.7). The cause of
Figure 48.6 Fibromuscular Dysplasia. Appearance of severe

fibromuscular dysplasia in extracranial internal and
external carotid arteries on conventional angiography. Note
the “string of beads” appearance with the characteristic
luminal narrowing alternating with aneurysmal dilatation.
Research.)
Figure 48.5 Magnetic Resonance Angiography of Carotid

Dissection. The flamelike tapering (arrow) of the internal
carotid artery suggests dissection.
Research.)
moyamoya disease has not been determined, but the dis-

ease has been associated with several conditions, includ-
ing autoimmune disease, phospholipid antibody syndrome,
sickle cell anemia, neurofibromatosis type 1, cranial irra-
diation, and Down syndrome. Patients often present in
childhood (mean age, 5 years) or in their 30s, and they
most commonly present with cerebral ischemia. For chil-
dren, the symptoms may be provoked by hyperventilation
or crying because of decreased cerebral perfusion. Adult
patients may also present with hemorrhage due to the fri-
ability of the collaterals. It is estimated that two-thirds of Figure 48.7 Moyamoya Disease. Conventional angiography
patients have progressive disease. For patients with cere- of the right internal carotid artery (ICA) shows the characteristic
bral ischemia, a “direct” procedure such as a superficial distal ICA stenosis (arrow) and the lenticulostriate collaterals
temporal artery–to–middle cerebral artery bypass is often (so-called puff of smoke) (arrowhead).
performed in combination with an indirect procedure such central nervous system vasculitis. Angiography often shows
as encephaloduroarteriosynangiosis. beading of the vessels with alternating stenosis and dilatation.
Although the beading appearance is classic, it is not diagnos-
Central Nervous System Vasculitis tic, and the differential diagnosis may also include vasospasm
(migraine, sympathomimetics, hypertensive crisis, or revers-
Isolated central nervous system vasculitis or systemic vas-
ible cerebrovasoconstrictive syndrome), sarcoid angiopathy,
culitides (polyarteritis nodosa, granulomatosis with poly-
infectious arteritis, radiation vasculopathy, atherosclerosis,
angiitis [formerly Wegener granulomatosis], systemic lupus
fibromuscular dysplasia, intravascular lymphoma, and lepto-
erythematosus, eosinophilic granulomatosis with polyangi-
meningitis. Brain biopsy in combination with leptomeningeal
itis [formerly Churg-Strauss syndrome], and cryoglobuline-
biopsy is the gold standard for diagnosis, but the findings can
mia) may affect the intracranial medium to large vessels.
be negative because of patchy involvement. Thus, negative
The arteries of the brain and spinal cord may be
biopsy findings do not completely exclude the diagnosis.
involved in isolated central nervous system (granuloma-
Treatment is generally with immunosuppressants, most com-
tous) angiitis. Pathologically, the blood vessels show evi-
monly cyclophosphamide and corticosteroids.
dence of inflammation, consisting of granulomas with
Other intracranial large-vessel disease includes reversible
multinucleated giant cells and lymphocytes (Figure 48.8).
cerebrovasoconstrictive syndrome, which is characterized by
Patients may present with cerebral ischemia, hemorrhage
thunderclap headaches, vasospasm, cerebral ischemia, and,
(rarely), seizures, encephalopathy, and headache.
sometimes, sulcal subarachnoid hemorrhage. Predisposing
In isolated central nervous system vasculitis, systemic
factors include the postpartum state, use of vasoactive sub-
markers such as sedimentation rate and C- reactive protein
stances (selective serotonin reuptake inhibitors, cannabis,
level are often normal. MRI may show areas of ischemia in
and sympathomimetics), and catecholamine- secreting
multiple territories and may show meningeal enhancement.
tumors. Angiography typically shows diffuse vasospasm (see
MRA may show diffuse irregularity of the large vessels, but
Chapter 100, “Secondary Headache Disorders”).
conventional angiography is superior for evaluation of isolated
A B
Figure 48.8 Primary Central Nervous System Vasculitis. A, Extensive leptomeningeal acute and chronic cellular infiltrates
and necrotizing vasculitis (arrows) of small leptomeningeal and parenchymal arteries. B, Classic angiographic appearance
of primary central nervous system vasculitis, with characteristic “beading” of vessels alternating stenosis and dilatation
(arrows), although this is not diagnostic by itself.
(From Flemming KD. Cerebrovascular disease. In: Mowzoon N, Flemming KD, editors. Neurology board review: an illustrated study
guide. Rochester [MN]: Mayo Clinic Scientific Press and Florence [KY]: Informa Healthcare USA; c2007. p. 435-84; used with permission
of Mayo Foundation for Medical Education and Research.)
Infectious arteritis is rare. It has been associated with Coagulation Disorders

herpes zoster ophthalmicus, hepatitis B and hepatitis C,
The overall pretest probability (ie, the prevalence) of a coagu-
HIV, cytomegalovirus, Epstein-Barr virus, bacterial aorti-
lation disorder as the cause of stroke is less than 5%. The
tis, and syphilis. Herpes zoster ophthalmicus can be asso-
pretest probability may increase among younger patients,
ciated with ipsilateral stenosis of the M1 segment of the
patients with malignancies, patients who are pregnant or are
middle cerebral artery. Cerebrospinal fluid studies may
taking a contraceptive, patients who have a history of miscar-
confirm the presence of virus, and treatment may be a
riages, patients with a personal or family history of a clotting
combination of acyclovir with or without corticosteroids
disorder, or patients with cryptogenic stroke. The differential
and antiplatelet agents.
diagnosis of clotting disorders is noted in Box 48.1. Testing
for all these patients should include a complete blood cell
• Intracranial atherosclerosis is the cause of 5% -7% of
count, erythrocyte sedimentation rate, partial thromboplastin
strokes.
time, and international normalized ratio. Selected patients
• The SAMMPRIS trial compared patients receiving
may need further testing, such as evaluation of coagulation
medical treatment (aspirin and clopidogrel for 90 days
factors, phospholipid antibodies (typically an arterial clot),
and risk factor management) with patients undergoing
lupus anticoagulant, β2-glycoprotein antibodies, factor V and
angioplasty and stenting for intracranial artery
prothrombin 20210 mutations (typically a venous clot), and
atherosclerosis plus medical management. The group
hemoglobin electrophoresis. Of note, if the level of protein C
that underwent angioplasty and stenting had a higher
or protein S is decreased at the time of an event, subsequent
rate of stroke, often perioperatively.
testing may be necessary to confirm its presence after 6 weeks.
• Isolated central nervous system vasculitis should be
Treatment varies depending on the cause.
considered for a patient with multifocal cerebral
ischemia, leptomeningeal enhancement, and headaches.
Sickle Cell Anemia
• Moyamoya disease is characterized by distal
Sickle cell anemia often results in stroke due to narrowing
intracranial, internal carotid artery stenosis with
or occlusion of the large cerebral arteries. By age 45 years,
resultant lenticulostriate collaterals that appear as
nearly one-fourth of patients may have had an ischemic
puffs of smoke on an angiogram.
stroke. Cerebral venous thrombosis and intracerebral hem-
• Herpes zoster ophthalmicus may result in ipsilateral
orrhage are less common. Transcranial Doppler ultrasonog-
M1 stenosis and stroke symptoms.
raphy may help to determine whether patients with sickle
cell anemia are at risk for cerebral ischemia by measuring
Small-Vessel Disease
blood flow velocities through intracranial vessels. Annual
Lacunar stroke (20% of strokes) refers to a small subcortical transcranial Doppler ultrasonography is generally recom-
infarction (<1.5 cm) resulting from the occlusion of a pen- mended for patients with sickle cell anemia who are older
etrating end artery. Examples of penetrating end arteries are than 2 years. For patients at high risk, exchange transfu-
basilar perforating vessels, lenticulostriate arteries, and sion is useful for preventing stroke.
thalamoperforate arteries. Thus, common locations of lacu-
nar strokes include the basal ganglia, thalamus, pons, and Antiphospholipid Antibody Syndrome
internal capsule. Pathologic findings are microatheroma, Antiphospholipid antibody syndrome should be consid-
lipohyalinosis, and fibrinoid necrosis. However, in about ered if a patient younger than 45 years has 1 or more
10% of persons with lacunar stroke, these pathologic find-
unexplained thrombotic events, an unexplained prolon-

ings are absent, raising the possibility of an embolic source. gation of the partial thromboplastin time, or thrombocy-
The most common risk factors are hypertension, smok- topenia and 1 or more adverse outcomes related to
ing, and diabetes mellitus. Numerous clinical lacunar syn- pregnancy. Evaluation should include phospholipid anti-
dromes exist; however, even the most experienced clinicians body, β2-glycoprotein antibody, and lupus anticoagulant
cannot always predict the localization on the basis of the testing. For patients with cryptogenic stroke and mini-
clinical syndrome alone. Thus, MRI may be useful to con- mally elevated or transient antibody levels, an antiplate-
firm the localization and topography. Treatment of typical let agent is recommended. For patients who meet criteria
lacunar disease is an antiplatelet agent and risk factor for antiphospholipid antibody syndrome, warfarin is
management. recommended.
Other disorders may result in strokes that appear to be
small-vessel strokes. These disorders include certain vasculiti- • The pretest probability of a coagulation disorder may
des, phospholipid antibody syndrome, and Behçet syndrome. increase among patients younger than 45 years with
cryptogenic stroke, patients with malignancies, patients
• Lacunar strokes account for approximately 20% of who are pregnant or are taking a contraceptive, patients
ischemic strokes. who have a history of miscarriages, or patients with a
• Common locations of lacunar strokes include the basal personal or family history of a clotting disorder, or a
ganglia, thalamus, pons, and internal capsule. combination of these.
Ischemic Stroke: Uncommon and Special
49 Situations
CATHERINE E. ARNOLD FIEBELKORN, MD; JAMES P. KLAAS, MD
Introduction clinically by migraine, stroke, mood disturbances, and

dementia. The defect is on chromosome 19 at 19q13.1 (a
M
ost ischemic stroke is caused by atherosclerosis missense mutation in the Notch3 gene). The Notch3 gene
(large-and small-vessel disease) and cardioem- encodes a transmembrane protein thought to be involved
bolic sources (eg, atrial fibrillation). However, it in cell signaling during embryonic development and is
is important to recognize the clinical, laboratory, and critical for vascular smooth muscle cell differentiation,
radiologic manifestations of rarer causes of stroke since vascular development, and vascular remodeling following
the treatment may differ from the treatment of more typi- injury. The mutation results in accumulation of the Notch3
cal causes. This chapter reviews the less common causes protein in the cytoplasmic membrane of vascular smooth
of stroke in addition to stroke in special situations: stroke muscle cells, pathologically resulting in widespread
in children, stroke in pregnant women, spinal cord infarc- myelin pallor of the white matter and multiple small
tion, and cerebral venous sinus thrombosis. infarcts in the white matter and basal ganglia.
Clinically, patients with CADASIL syndrome regularly
have migraine headaches with aura in their youth, recur-
Uncommon Genetic Causes of Stroke rent stroke or strokelike episodes in their 40s to 60s (often
in the absence of conventional risk factors), and often a
A number of heritable conditions may include cerebral progressive dementia. Psychiatric disturbances, especially
ischemia among the clinical manifestations. These condi- mood disturbances, are also relatively common. Other
tions are discussed below and summarized in Table 49.1. clinical symptoms may include pseudobulbar affect, uri-
nary incontinence, gait disturbance, and upper motor neu-
Cerebral Autosomal Dominant Arteriopathy ron signs.

With Subcortical Infarcts and The diagnosis can be made by pedigree analysis (family
Leukoencephalopathy Syndrome history), typical magnetic resonance imaging (MRI) find-
Cerebral autosomal dominant arteriopathy with subcorti- ings, skin biopsy, or genetic testing. MRI of the brain gener-
cal infarcts and leukoencephalopathy (CADASIL) syn- ally shows confluent deep white matter changes often
drome is an autosomal dominant condition characterized involving the anterior temporal lobes (Figure 49.1). Skin
The editors and authors acknowledge the contributions of Kelly D. Flemming, MD, to the previous edition of this chapter.
Abbreviations: CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy;
CARASIL, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; CT, computed
tomography; MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes; MRI, magnetic
resonance imaging; TIPS, Thrombolysis in Pediatric Stroke; tPA, tissue plasminogen activator
399
Table 49.1 • Genetic Causes of Cerebral Ischemia

Condition Genetic Features Key Features
CADASIL syndrome Autosomal dominant Migraine

Mutation in Notch3 gene at 19q13.1 Transient ischemic attack or stroke
Dementia
Extensive leukoaraiosis involving temporal lobes
Marfan syndrome Autosomal dominant Ischemic stroke
Mutation in fibrillin 1 (FBN1) gene (usually) at 15q-21.1 Cerebral aneurysms possible
MELAS syndrome Mutations in genes of mitochondrial DNA Encephalopathy
Seizures
Ischemic stroke
Deafness
Myopathy (ragged red fibers on biopsy)
Short stature
Elevated level of lactic acid
Fabry disease X-linked Deficiency of α-galactosidase
Mutations in the α-galactosidase A gene at Xq22.1 Cutaneous angiokeratomas
Lens opacities
Painful paresthesias
Stroke (posterior circulation)
Vertebrobasilar arterial dilatation/dolichoectasia
Abbreviations: CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; MELAS, mitochondrial
myopathy, encephalopathy, lactic acidosis, and stroke-like episodes.
A B
Figure 49.1 CADASIL Syndrome. Magnetic resonance imaging of the brain shows a T2 signal change in the anterior
temporal lobes (A) and deep white matter (B) consistent with the diagnosis of CADASIL syndrome. CADASIL indicates
cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.
Chapter 49. Ischemic Stroke: Uncommon and Special Situations 401
biopsy may show granular osmophilic material with elec- rare disorder of mitochondrial DNA. Most cases result
tron microscopy. from a point mutation, from A to G, in the dihydrouridine
No current treatment is known to delay progression of loop of the transfer RNA gene at mt3243. Clinically,
the disease. Antithrombotics, such as aspirin, are typically patients may present variably with a combination of pro-
used to prevent ischemic stroke. gressive encephalopathy, seizures, ischemic stroke, deaf-
ness, and myopathy.
Cerebral Autosomal Recessive Arteriopathy With The diagnosis of MELAS syndrome is made through
Subcortical Infarcts and Leukoencephalopathy several investigations. MRI of the head often shows isch-
Syndrome emic areas crossing arterial boundaries (Figure 49.2). In
addition, patients may have basal ganglia calcification.
Cerebral autosomal recessive arteriopathy with subcortical
They may have an elevated level of blood lactic acid and
infarcts and leukoencephalopathy (CARASIL) syndrome,
an increased lactate to pyruvate ratio. Similarly, in the
an autosomal recessive variant, has been described.
cerebrospinal fluid, the lactate level may be elevated.
CARASIL syndrome results from mutations in the HTRA1
Muscle biopsy may show ragged red fibers in skeletal mus-
gene and differs from CADASIL syndrome in its inheri-
cle. Molecular genetic analysis and magnetic resonance
tance pattern. Patients with CARASIL syndrome often
spectroscopy of the brain can also be performed to secure
have an associated alopecia, lumbar spondylosis, and epi-
the diagnosis.
sodes of acute low back pain.
Treatment of MELAS syndrome is supportive, and the
disease is progressive. l-arginine and coenzyme Q10 are
Marfan Syndrome
often used. Valproic acid should be avoided in patients
Marfan syndrome is an autosomal dominant condition that with mitochondrial disorders, should seizures occur,
may also predispose a patient to stroke and cerebrovascular because of interference with the respiratory chain function.
disease. The defect is in the FBN1 gene that encodes the
connective protein fibrillin 1. Patients may have ischemic Fabry Disease
stroke related to mitral or aortic valve disease, aortic dissec-
tion, and a predisposition to cerebral aneurysm formation. Fabry disease is an X-linked lysosomal storage disorder
secondary to a mutation in the GLA gene resulting in a defi-
Pseudoxanthoma Elasticum ciency of α-galactosidase. Male persons are hemizygous for
the mutation and therefore often present clinically with
Pseudoxanthoma elasticum is an autosomal recessive dis- the classic signs and symptoms of cutaneous angiokerato-
ease of connective tissue characterized by progressive dys- mas (Figure 49.3), corneal and lenticular opacities, deaf-
trophic mineralization of elastic fibers within the skin, ness, and often painful paresthesias. Female persons, who
retina, and arterial walls. Clinically, patients have skin are heterozygous for the mutation, present with a range of
lesions (yellow or orange papules) and increased laxity phenotypes from asymptomatic carriers, which is most
and redundancy of skin. They may have loss of visual acu- common, to a more severe syndrome similar to male per-
ity, cardiovascular and cerebrovascular complications, sons, thought to be related to a process known as X chro-
ischemic stroke, a syndrome resembling Binswanger mosome inactivation. Ischemic stroke can occur, more
disease, and a predisposition to aneurysm formation. often involving the posterior circulation, and patients are
also prone to coronary and renal artery disease.
Vascular Type of Ehlers-Danlos Syndrome
Neurovascular imaging may show dilatation or dolichoec-

The vascular type of Ehlers-Danlos syndrome (formerly type tasia of the vertebrobasilar arteries, and leukoaraiosis.
IV) is an autosomal dominant disorder due to a mutation of Patients with Fabry disease should receive α-galactosidase
the gene that encodes type III procollagen. Patients with this replacement therapy.
disorder are predisposed to rupture of arteries, the bowel,
and the uterus. Cerebrovascular complications include a Inflammatory and Noninflammatory Arteriopathies
predisposition to intracranial aneurysm formation, arterial
Rare inflammatory and noninflammatory causes of stroke
dissection, and possible carotid-cavernous fistula.
are noted in Table 49.2.
Mitochondrial Myopathy, Encephalopathy, • CADASIL syndrome is an autosomal dominant

Lactic Acidosis, and Stroke-like Episodes condition characterized clinically by migraine, stroke,
Syndrome and dementia.
Mitochondrial myopathy, encephalopathy, lactic acidosis, • Clinically, patients with CADASIL syndrome often
and stroke-like episodes (MELAS) syndrome is caused by a have migraine headaches in their youth and stroke or
A B C
D E F
Figure 49.2 MELAS Syndrome. Magnetic resonance imaging (MRI) shows evidence of an old inferior left temporal and
occipital stroke on fluid-attenuated inversion recovery images (A-C) and, with diffusion-weighted imaging, a new lesion in the
right temporal and occipital areas (D-F). This patient also had short stature, hearing loss, and a history of seizure. The MRI
pattern crosses typical arterial boundaries and is consistent with MELAS syndrome. MELAS indicates mitochondrial
myopathy, encephalopathy, lactic acidosis, and stroke-like episodes.
stroke-like episodes in their 40s to 60s, followed by Special Situations in Stroke

progressive dementia.
• MRI of the brain of a patient who has CADASIL Stroke in Children
syndrome generally shows confluent deep white Stroke in childhood is rare but devastating. The incidence
matter changes, often involving the anterior is 2 to 10 cases per 100,000 children per year. In adults,
temporal lobes. 80% of strokes are ischemic; in children, 55% are ischemic
• Patients with MELAS syndrome may present variably and 45% are hemorrhagic.
with a combination of progressive encephalopathy, Perinatal stroke is generally defined as any hemor-
seizures, ischemic stroke, deafness, and myopathy. rhagic or ischemic event occurring from 20 weeks of gesta-
• Patients with Fabry disease should receive tion through the first 28 days of life. Cerebral ischemia,
α-galactosidase replacement therapy. hemorrhage, and venous thrombosis can occur. Focal
One-half occur within the first 24 hours and 90% within

the first 72 hours after birth. The hemorrhage occurs in the
subependymal germinal matrix, often in the region of the
caudate near the foramen of Monro (Figure 49.4).
Hemorrhages are often graded according to severity (Table
49.3). Patients may be asymptomatic (grade 1) or have
acute neurologic deterioration with coma, stupor, tense
fontanelle, apnea, bradycardia, and hypotension. Muscle
tone changes, seizures, and pupillary changes may also
occur. Treatment is generally supportive and aimed at
reducing complications of the hemorrhage, including post-
hemorrhagic hydrocephalus. Patients with grade 1 or grade
2 hemorrhage have a good prognosis.
For children, 30% of ischemic strokes are cryptogenic.
The most common causes of stroke in children are acquired
or congenital heart disease and sickle cell anemia.
Arteriopathies are also similarly common. The differential
diagnosis of stroke in children is detailed in Box 49.1.
The safety and efficacy of acute stroke therapy for chil-
dren have not been established. Case reports of selected
patients have shown potential efficacy with intravenous
thrombolytics; however, the safety has not been proven.
Thrombolysis in Pediatric Stroke (TIPS) was a safety and
dose-finding study of intravenous tissue plasminogen acti-
vator (tPA) therapy for children with acute ischemic stroke.
However, lack of patient accrual resulted in the study
being terminated. Therefore, tPA is generally not recom-
mended for children with acute ischemic arterial stroke.
No consensus exists about tPA use for older adolescents
who otherwise meet standard adult tPA eligibility criteria.
Similarly, the safety and efficacy of mechanical thrombec-
tomy in children younger than 18 years are unknown, but
Figure 49.3 Fabry Disease. Cutaneous angiokeratomas are this treatment can be considered on an individual basis for
common in Fabry disease. some children with a documented anterior circulation
large-vessel occlusion.
The use of anticoagulation and antiplatelet agents for
deficits, altered mental status, or seizures may be the pre-
stroke in pediatric patients is highly individualized and
senting signs. Risk factors include cardiac disorders, coag-
beyond the scope of this text.
ulation disorders, infection, trauma, certain medications,
maternal disorders, and perinatal asphyxia.
• Perinatal stroke is generally defined as any

Cranial ultrasonography, computed tomography (CT),
hemorrhagic or ischemic event occurring from 20
or MRI may be used to diagnose stroke in neonates. MRI
weeks of gestation through the first 28 days of life.
has superior sensitivity and specificity for detecting isch-
• Periventricular-intraventricular hemorrhage can occur
emia and cerebral venous sinus thrombosis.
in up to 40% of premature neonates weighing
The choice of treatment depends on the potential cause.
<1,500 g.
In neonates with intracranial hemorrhage, coagulation dis-
• The most common causes of stroke in children are
orders should be corrected and surgery or ventricular drain-
acquired or congenital heart disease and sickle cell
age performed as necessary. Anticoagulation is considered
anemia.
in selected patients with severe thrombophilic disorders,
multiple systemic emboli, or progressive propagation of
Stroke in Pregnancy
venous sinus thrombosis.
Periventricular-intraventricular hemorrhage can occur Pregnancy is a special situation in which the body is pre-
in up to 40% of premature neonates born before 32 weeks’ paring for an event that requires rapid coagulation at the
gestation or weighing less than 1,500 g. The incidence time of birth. A number of changes occur during pregnancy
increases with decreasing gestational age and birth weight. and the puerperium. Typically, changes begin in the first
Table 49.2 • Rare Inflammatory and Noninflammatory Causes of Stroke
Condition Clinical Characteristics Diagnosis Treatment
Cogan syndrome Interstitial keratitis or scleritis Clinical picture Immunosuppressants

Hearing loss or vestibular Eye examination
symptoms Rule out other vasculitides
Stroke
Systemic symptoms
Eales disease Stroke Clinical presentation Immunosuppressants may be
Young adults Fluorescein angiography considered
Visual loss with retinal vasculitis Rule out other systemic vasculitides
(veins or arterioles), vitreous
hemorrhage, microaneurysms of
retinal vessels
Late complications:
neovascularization, retinal
detachment, glaucoma
Susac syndrome Acute to subacute encephalopathy, Clinical picture Immunosuppressants
(retinocochleo- vision loss, and sensorineural MRI: multiple, small, punctate areas Plasma exchange or IVIG
cerebral hearing loss of T2 signal increase; contrast
vasculopathy) Cerebral symptoms: behavioral, enhancement in cerebral gray
affect, cognitive dysfunction, matter and in white matter
ataxia, corticospinal tract Lesions often involve corpus
involvement callosum
Ophthalmologic findings: visual Pathologic features: microangiopathy
field losses; retinal arteriolar affecting the arterioles of the
stenosis or occlusions brain, retina, and cochlea; some
Otologic findings: low-to mid- perivascular lymphocytic
frequency sensorineural hearing infiltration, but not definitively
loss vasculitic
Rule out other vasculitides
Sneddon syndrome Livedo reticularis (reticulated skin Clinical picture Antithrombotics (antiplatelet
pattern caused by impaired Livedo reticularis may be associated agents or warfarin) may be
superficial venous drainage of with other entities; rule out considered
the skin) systemic vasculitides
Ischemic stroke Sneddon syndrome may coexist with
Seizures antiphospholipid antibody
Dementia syndrome
Pathologic features: vasculopathy
without vasculitis has been found
on brain biopsies; skin biopsy
may show noninflammatory
vasculopathy of medium-sized
arteries with intimal hyperplasia;
microvascular thromboses
Kohlmeier-Degos Skin manifestations: raised Pathologic features: occlusive Unclear
disease (malignant papules with white center vasculopathy of the skin, cerebral
atrophic papulosis) Cerebral ischemia circulation, and other organs;
fibrous intimal proliferation
accompanied by thrombosis
Isolated CNS vasculitis Ischemic stroke Systemic markers are negative Glucocorticoids
(granulomatous Seizures MRI: cerebral ischemia; with or Cyclophosphamide
vasculitis) Headache without leptomeningeal
enhancement
CSF: mildly increased white blood
cell count and protein level
Cerebral angiography: beading of
vessels
Brain biopsy: granulomatous
vasculitis
Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; IVIG, intravenous immunoglobulin; MRI, magnetic resonance imaging.
A B
Figure 49.4 Periventricular-Intraventricular Hemorrhage. A, Coronal section shows a typical periventricular-intraventricular

hemorrhage (grade 1) involving the germinal matrix overlying the caudate head, rostral to the foramen of Monro. B,
Postmortem specimen from a different neonate shows a larger hemorrhage (grade 4) extending into the brain parenchyma
and lateral ventricle.
(From Okazaki H, Scheithauer BW. Atlas of neuropathology. New York [NY]: Gower Medical Publishing; c1988. Chapter 8, Perinatal CNS
injuries and congenital malformations; p. 277-94; used with permission of Mayo Foundation for Medical Education and Research.)
trimester and continue into late pregnancy (Box 49.2). The uteroplacental circulation while preventing fibrin deposi-
red blood cell mass increases at about 10 weeks and con- tion in the rest of the vascular system.
tinues to increase progressively until term. The plasma Cerebrovascular complications during pregnancy and
volume begins to increase also at about 10 weeks’ gesta- the postpartum state include subarachnoid hemorrhage,
tion, continues to increase progressively until 30 to 34 intraparenchymal hemorrhage, venous thrombosis, pitu-
weeks, and then plateaus. The mean increase in plasma itary apoplexy, ischemic stroke, and reversible vasocon-
volume by 30 to 34 weeks is 50%. Because volume strictive syndrome (peripartum angiopathy) (Table 49.4).
increases by 50% and the red blood cell mass increases by
only 18% to 30%, the hematocrit decreases to its nadir at Spinal Cord Infarction
30 to 34 weeks, resulting in anemia.
Spinal cord infarction is rare. Mechanisms include hypo-
When the placenta separates, maternal blood flow (700
perfusion, embolism, and thrombosis. The thoracolumbar
mL/ min) is reduced by myometrial compression and
segment is most vulnerable to hypoperfusion. The differ-
thrombotic occlusion of the vessels. Coagulation is acti-
ential diagnosis of spinal cord infarction is listed in
vated, and fibrinogen increases while coagulation inhibi-
Table 49.5.
tors decrease. The coagulation and fibrinolytic systems are
Patients with spinal cord infarction typically present
important in controlling fibrin deposition in the
with an anterior spinal artery syndrome; posterior spinal

artery syndrome and sulcal artery syndrome are less com-
mon. With anterior spinal artery syndrome, the posterior
columns are spared. Thus, clinical examination may
Table 49.3 • Grading of Periventricular-Intraventricular
show loss of pain and temperature sensation below the
Hemorrhage of the Germinal Matrix
level of the lesion with sparing of vibratory and joint
Grade Description position sensation, upper motor neuron loss below the
1 Confined to caudate head and subependymal layer
level of the lesion, and lower motor neuron function loss
(usually asymptomatic) at the segment of the injury. Autonomic dysfunction may
also occur.
2 Extension into lateral ventricle without
ventriculomegaly Diagnosis is made with a combination of the history,
imaging studies, and a ruling out of alternative causes
3 Extension into lateral ventricle with ventriculomegaly
(Box 49.3). MRI of the spine (or, alternatively, CT
4 Extension into parenchyma myelography) may be helpful to rule out other causes of
Box 49.1 • Differential Diagnosis of Stroke Among Cardiac Disorders in Children
Cardiac disorders Hypercoagulable states

Congenital heart disease Primary hypercoagulable states
Transposition of the great vessels Antithrombin III, protein C, or protein S deficiency
Atrial or ventricular septal defect Factor V Leiden or prothrombin 20210 mutation
Patent foramen ovale Disorders of fibrinogen or plasminogen activator
Pulmonary stenosis inhibitor
Tetralogy of Fallot Antiphospholipid antibody syndrome
Truncus arteriosus with decreased flow Increased factor VII, VIII, or XII
Patent ductus arteriosus Secondary (acquired) hypercoagulable states
Endocardial cushion defect Malignancy
Hypoplastic left ventricle Pregnancy
Ebstein anomaly Oral contraceptive
Pulmonary atresia Ovarian hyperstimulation syndrome
Coarctation of the aorta Hormonal treatments (erythropoietin, anabolic
Valvular heart disease steroids)
Congenital Nephrotic syndrome
Rheumatic Polycythemia vera
Prosthetic valve Essential thrombocytopenia
Mitral valve prolapse Paroxysmal nocturnal hemoglobinuria
Infective endocarditis or noninfective endocarditis Hyperlipidemia, elevated lipoprotein (a) level
Aneurysm of the sinus of Valsalva Heparin-induced thrombocytopenia
Cardiac arrhythmias Homocystinuria
Atrial fibrillation
Sickle cell disease
Supraventricular tachycardia
Thrombotic thrombocytopenic purpura
Sick sinus syndrome
Chemotherapeutic agents
Cardiomyopathy
Kearns-Sayre syndrome Miscellaneous and genetic risk factors for stroke
Myocardial infarction Hereditary dyslipoproteinemia (familial
Left ventricular aneurysm hypoalphalipoproteinemia, familial
Intracardiac tumors hypercholesterolemia, type III or IV
Muscular dystrophy hyperlipoproteinemia, Tangier disease, progeria)
Myocarditis Heritable disorders of connective tissue (vascular type of
Ehlers-Danlos syndrome, Marfan syndrome,
Friedreich ataxia
pseudoxanthoma elasticum, homocystinuria, Menkes
Cardiac surgery and catheterization syndrome)
Extracorporeal membrane oxygenation Organic acidemias (methylmalonic acidemia, propionic
Kawasaki disease acidemia, isovaleric acidemia, glutaric aciduria type II)
Arteriopathies Mitochondrial encephalomyopathy (MELAS syndrome,
Dissection MERRF syndrome, Kearns-Sayre syndrome)

Moyamoya disease Fabry disease (α-galactosidase A deficiency)
Fibromuscular dysplasia Leigh disease (subacute necrotizing
Vasculitis encephalomyelopathy)
Transient cerebral arteriopathy Sulfite oxide deficiency
Postvaricella angiopathy 11β-ketoreductase deficiency
Migrainous infarction 17α-hydroxylase deficiency
Ergotism Purine nucleoside phosphorylase deficiency
Traumatic Ornithine transcarbamylase deficiency
Radiation-induced Neurofibromatosis type 1
Tumor-encased arteries HERNS syndrome
Hypoplasia or agenesis of cervicocephalic vessels
Abbreviations: HERNS, hereditary endotheliopathy with retinopathy, nephropathy, and stroke; MELAS, mitochondrial myopathy,
encephalopathy, lactic acidosis, and stroke-like episodes; MERRF, myoclonic epilepsy with ragged red fibers.
Modified from Biller J, Schneck MJ, Love BB. Cardiac disorders and stroke in children and young adults. In: Biller J, editor. Stroke in
children and young adults. 2nd ed. Philadelphia (PA): Saunders/Elsevier; c2009. p. 135-59; used with permission.
potential during aortic surgery and the avoidance of

Box 49.2 • Changes in Specific Coagulation Factors hypotension. For the acute infarction, methylpredniso-
in Pregnancy lone administration and lumbar cerebrospinal fluid
drainage to reduce intrathecal pressure have been tried
with variable success. Secondary prevention is based on
Increased
treatment of the probable cause. Supportive treatment
Fibrinogen (doubles) with rehabilitation and careful bowel and bladder man-
Factors VII, VIII, X, and XII agement is important.
Plasminogen (50%) The prognosis is variable, depending on the location
PAI-1 and PAI-2 and degree of damage and the cause. Among patients,
Blood volume 20% to 25% have no improvement, 20% have good
D-dimer recovery with minimal disability, and the other patients
β-Thromboglobulin (platelet) have a poor prognosis. Chronic pain can be a disabling
Fibrinopeptide A (first peptide cleaved from fibrinogen) feature.
Decreased • Patients with spinal cord infarction typically present

with an anterior spinal artery syndrome.
Factors XI and XIII
Platelets (possibly)
Cerebral Venous Sinus Thrombosis
Fibrinolytic systems (highest in third trimester)
Tissue plasminogen activator Cerebral venous sinus thrombosis is less common than
arterial stroke. The differential diagnosis includes malig-
Free protein S
nancy, pregnancy or the postpartum state, oral contracep-
No change tion, factor V Leiden (common), hyperhomocysteinemia,
prothrombin 20210 mutation, protein C or protein S defi-
Factors II, V, and IX
ciency, contiguous infectious extension, dural arteriove-
Angiotensin III nous fistula, phospholipid antibody syndrome, essential
Total protein S thrombocytosis, or polycythemia vera. For children,
Protein C dehydration, infection, and sickle cell anemia should also
be considered. A list of potential risk factors and condi-
Abbreviation: PAI, plasminogen activator inhibitor.
tions resulting in venous thrombosis is presented in
Table 49.6.
From Flemming KD. Cerebrovascular disease. In: Mowzoon N,
Flemming KD, editors. Neurology board review: an Patients with cerebral venous sinus thrombosis typi-
illustrated study guide. Rochester (MN): Mayo Clinic cally present with subacute, progressive headache, but
Scientific Press and Florence (KY): Informa Healthcare
they may rarely have thunderclap headache. Since they
USA; c2007. p. 435-84; used with permission of Mayo
Foundation for Medical Education and Research. have increased intracranial pressure, patients may have
papilledema, cranial nerve VI palsy, and transient visual
obscurations (graying of vision bilaterally, often with
sneezing or straining). Patients may also have focal neuro-
logic deficits or seizures if cerebral venous congestion,
infarction, or hemorrhage occurs.

myelopathy. MRI may also show increased T2 signal The diagnosis can be made with magnetic resonance
intensity or restricted diffusion in the spinal cord. venography, CT venography, or conventional angiography
Further evaluation for potential causes may depend on (Figure 49.5).
history and recent procedures. Evaluation could include Anticoagulation is generally recommended and is not
a search for aortic disease, cardioembolic disease, coag- contraindicated in the cases of hemorrhagic venous infarc-
ulopathies, or vasculitides, depending on the pretest tion. Mechanical clot disruption or interventional adminis-
probability. tration of thrombolytics can be considered if the patient has
No clinical trials guide treatment of spinal cord an increased intracranial pressure that cannot be controlled
infarction. Prevention of stroke during major abdominal or is not responding to anticoagulation or if the patient is
aortic surgical procedures is common, with the use of somnolent. The duration of anticoagulation treatment
intraoperative monitoring with somatosensory- evoked depends on the identified cause. If no specific entity is
Table 49.4 • Cerebrovascular Complications During Pregnancy and the Postpartum Period
Complication Incidence Causes Comments
Subarachnoid 5–20 per 100,000 Aneurysm More common during

hemorrhage deliveries AVM pregnancy than in
Trauma postpartum period
Intraparenchymal 5–10 per 100,000 AVM More common in postpartum
hemorrhage deliveries Cavernous malformation period than during
Eclampsia pregnancy
Venous thrombosis
Venous thrombosis 10–20 per 100,000 May have predisposing factor (eg, factor V Leiden 80% are in postpartum period
deliveries mutation, dehydration, infection, sickle cell anemia) Low recurrence risk
Pituitary apoplexy Rare Preexisting pituitary adenoma NA
Arterial stroke 3.5–10 per 100,000 May be unrelated to pregnancy More common in postpartum
deliveries Specific rare causes of pregnancy-related stroke: period than during
eclampsia, choriocarcinoma, amniotic fluid embolism, pregnancy
reversible cerebrovasoconstrictive syndrome,
peripartum cardiomyopathy
Reversible Rare Concomitant use of sympathomimetics and selective More common in postpartum
vasoconstrictive serotonin reuptake inhibitors period than during
syndrome pregnancy
Abbreviations: AVM, arteriovenous malformation; NA, not applicable.
Box 49.3 • Proposed Criteria for SCI Diagnosis and

Types of SCI
Table 49.5 • Differential Diagnosis of Spinal Cord
Infarction Criteria for SCI
Etiologic Factor Conditions 1. Acute nontraumatic myelopathy (no preceding
progressive myelopathy)
Vasculitis Polyarteritis nodosa, Behçet syndrome, Onset to nadir severe deficits, 12 h or less
giant cell arteritis If stuttering course is more than 12 h, severe deficits
Embolism Atrial myxoma, mitral valve disease, rapidly develop within 12 h or less
endocarditis, paradoxical emboli, 2. Magnetic resonance imaging
fibrocartilaginous emboli from
A. No spinal cord compression
herniated disks
B. Supportive findings:
Systemic Cardiopulmonary arrest, aortic rupture
Intramedullary T2 hyperintense spinal cord lesion
hypoperfusion or dissection, coarctation of aorta
C. Specific findings (1 of):
Iatrogenic cause Thoracolumbar sympathectomy,
Diffusion-weighted imaging or apparent diffusion
scoliosis surgery, cardiac
coefficient restriction;
catheterization, aortography, renal
artery embolization, umbilical artery Associated vertebral body infarction;
catheterization, vertebral Arterial dissection or occlusion adjacent to lesion
angiography, aortic surgery, surgical 3. Cerebrospinal fluid

repair of coarctation, retroperitoneal
Noninflammatory (normal cell count,
lymph node dissection
immunoglobulin G index, and no
Infectious disease Syphilis, mucormycosis, meningitis oligoclonal bands)
Miscellaneous cause Sickle cell anemia, cocaine or heroin 4. Alternative diagnosis is less likely
use, decompression sickness,
antiphospholipid antibody Types of SCI
syndrome, Crohn disease, cervical 1. Definite spontaneous (1, 2A, 2B, 2C, and 4)
subluxation, atherosclerosis of the
2. Probable spontaneous (1, 2A, 2B, 3, and 4)
aorta, venous infarction
3. Possible spontaneous (1 and 4)
4. Definite periprocedural (1, 2A, 2B, and 4)
5. Probable periprocedural (1 and 4)
Abbreviations: h, hour; SCI, spinal cord infarction.
Modified from Zalewski NL, Rabinstein AA, Krecke KN, Brown RD Jr,
Wijdicks EFM, Weinshenker BG, et al. Characteristics of
spontaneous spinal cord infarction and proposed diagnostic criteria.
JAMA Neurol. 2019 Jan 1;76(1):56-63; used with permission.
Table 49.6 • Risk Factors for Cerebral Venous Sinus A

Thrombosis
Risk Factor Conditions
General disorder Dehydration

Lumbar puncture or overshunting
(ie, excessive drainage of
cerebrospinal fluid)
Hypoxia
Head trauma
Infection Meningitis
Mastoiditis
Ear infections
Tonsillitis
Sinusitis
Blood disorder Essential thrombocytosis
Heparin-induced thrombocytopenia
Polycythemia vera
Sickle cell anemia
Lymphoma
Iron deficiency anemia
Autoimmune hemolytic anemia
Paroxysmal nocturnal
hemoglobinuria
Thalassemia
Coagulation disorder Prothrombin 20210 mutation
B
Factor V Leiden mutation
Protein C or protein S deficiency
Antithrombin III deficiency
Phospholipid antibody syndrome
Homocystinuria
Drug or toxin Certain chemotherapeutic agents
Estrogens
Corticosteroids
Epoetin alfa
Systemic disease Malignancy
Systemic lupus erythematosus
Thyrotoxicosis
Behçet syndrome
Inflammatory bowel disease
(ulcerative colitis, Crohn disease)
Nephrotic syndrome
identified, anticoagulation is generally recommended for 3

to 6 months with follow-up imaging at that time.
• Patients with venous thrombosis typically present

Figure 49.5 Venoocclusive Disease and Venous Infarction.
with subacute progressive headache, but they may
The patient was a 47-year-old woman who was taking oral
rarely have thunderclap headache.
contraceptives. A, Magnetic resonance (MR) venography
• Anticoagulation is the treatment of choice even if
shows extensive thrombosis of the left transverse and sigmoid
venous hemorrhages are present.
sinuses that extends to involve the left internal jugular vein.
B, Nonenhanced T1-weighted MR imaging shows hemorrhagic
venous infarction in the left temporal lobe.
Flemming KD, editors. Neurology board review: an illustrated study
guide. Rochester [MN]: Mayo Clinic Scientific Press and Florence
[KY]: Informa Healthcare USA; c2007. p. 435- 84; used with
permission of Mayo Foundation for Medical Education and Research.)
Acute Ischemic Stroke Evaluation
50 and Treatment
EUGENE L. SCHARF, MD
Introduction when the patient was last seen to be well (last known well)
and to obtain a blood glucose level.
A
cute ischemic stroke is a neurologic emergency
where an estimated 2 million neurons a minute
are lost secondary to ischemia. Treatments of Emergency Department Evaluation
acute stroke are directed at early revascularization of the
Emergency department treatment of patients with acute
occluded vessel and to preserve neuronal death and
stroke consists of multiple simultaneous assessments in a
improve collateral flow. Treatments are time sensitive, an
critical care bay. Emergency department physicians assess
aspect that places great importance on early symptom rec-
the patient’s clinical stability and medical comorbidities,
ognition, correct diagnosis, and clinical management. In
obtain vital signs, gain intravenous (IV) access, and per-
acute ischemic stroke, in short, “time is brain.”
form laboratory tests. An electrocardiogram and a chest
radiograph can be obtained, but they should not delay neu-
rologic assessment and acute stroke treatment decisions.
Acute Clinical Evaluation General principles of the medical management of stroke
are summarized in Box 50.1.
Emergency Medical Services
A neurologist or a qualified physician (either on-site or
Early activation of emergency medical services (EMS) by through telemedicine) should next perform a rapid history
witnesses is the first link in the chain of survival in stroke focused on the time of symptom onset (last known well)
care. EMS personnel will evaluate a person in whom an and any known contraindications to IV thrombolysis.
ischemic stroke is suspected and will provide first- Next, a neurologic assessment of the patient’s clinical defi-
responder level of care, including evaluation of vital signs, cits and their severity is performed with the standardized
blood glucose, prehospital stroke assessment scale, and a and widely accepted National Institutes of Health Stroke
brief history if possible (Figure 50.1). The recommendation Scale (NIHSS). The NIHSS score can be obtained in a few
for a patient presenting with signs and symptoms of stroke minutes and provides crucial information to the localiza-
is transportation to a certified stroke center. EMS personnel tion and severity of the potential stroke (Table 50.1).
will initiate prenotification to the accepting emergency After these rapid assessments, the patient should receive
department. Of importance, when interacting with EMS non–contrast medium computed tomography (CT) of the
personnel, the treating physician or neurologist, or both, head for the purpose of excluding radiographic contraindi-
needs to note either the time of symptom onset or the time cations to thrombolysis (eg, intracranial hemorrhage, mass
Abbreviations: ASPECTS, Alberta Stroke Program Early Computed Tomography Score; CT, computed tomography; EMS, emergency
medical services; EVT, endovascular therapy; FDA, US Food and Drug Administration; IV, intravenous; MRI, magnetic resonance imag-
ing; mRS, modified Rankin scale; NIHSS, National Institutes of Health Stroke Scale; r-tPA, recombinant tissue plasminogen activator
410
Stroke Symptoms
911 call and EMS transport
Emergency department evaluation STAT

Neuro consult performs NIHSS assessment
STAT head CT
Yes Manage per

Hemorrhage
type and guideline
No
Administer Yes No Suspicion that

IV thrombolytic
EVT
IV thrombolytic candidate?
candidate?
Suspicion that Yes STAT head and Yes No Admit to

EVT neck CTA (often Neuro
candidate? done with head CT) ICU
No
Admit to Large-vessel No Admit to

Neuro ICU occlusion? Neuro ICU
Yes
Admit to No <6-h onset and No Admit to

6-24–h onset?
Neuro ICU meets EVT criteria? Neuro ICU
Yes Yes
Yes Extended-window No
EVT
EVT criteria?
Admit to
Neuro ICU
Figure 50.1 Management of Acute Ischemic Stroke. Evolving data at the time of this writing are assessing whether select
candidates may go direct to EVT. CT indicates computed tomography; CTA, computed tomographic angiography; EMS,
emergency medical services; EVT, endovascular therapy; ICU, intensive care unit; IV, intravenous; Neuro, neurosciences;
NIHSS, National Institutes of Health Stroke Scale; STAT, without delay.
IV thrombolysis, although not approved in the United

Box 50.1 • Principles of Medical Management of States, may be offered in an extended window of symptom
Acute Ischemic Stroke duration between 3 and 4.5 hours unless any of the follow-
ing characteristics are present: age 80 years or older, NIHSS
Administer supplemental oxygen through nasal
score of 25 or more, a history of diabetes mellitus and prior
cannula if hypoxia (oxygen saturation <94%) is
present stroke, or a history of anticoagulant use regardless of inter-
Hypoglycemia should be treated if glucose <60 mg/dL national normalized ratio. In the 2018 American Stroke
Association guidelines, the benefit of IV r-tPA for patients
Hyperglycemia should be treated to a glucose range of
140-180 mg/dL presenting 3 to 4.5 hours earlier with an NIHSS of 25 or
Maintain euvolemia with IV crystalloid; avoid more was uncertain, but the other criteria were not consid-
dextrose-containing fluids ered as strongly in the extended time window.
Permissive hypertension is <220/110 mm Hg without Of note, thrombolysis should not be delayed secondary to
IV thrombolytics waiting for laboratory test results unless there is reasonable
Permissive hypertension is <185/110 mm Hg during clinical suspicion of an abnormality that would otherwise be
or after IV thrombolytic or if patient is a candidate a contraindication. Unexpected coagulopathies or cytopenias
for thrombolytic therapy are rare in an undifferentiated population. The only labora-
Monitor cardiac function tory test necessary to review before thrombolysis is a blood
Fever and hyperthermia (>38°C) should be treated with glucose level, which can be obtained at the point of care.
antipyretics Contraindications to thrombolysis are absolute and rela-
Acute BP goal is <220/110 mm Hg (without tive (Box 50.2). IV r-tPA should not be offered to anyone with
IV thrombolytic) or <185/110 mm Hg (with an absolute contraindication. As of the time of this writing,
IV thrombolytic or if patient is a candidate for
IV r-tPA should not be administered to patients who wake
thrombolytic therapy)
up with strokelike symptoms outside the conventional time
Maintain NPO until swallow can be safely determined
window without advanced imaging and careful selection or
If IV thrombolytics were administered or mechanical
as part of a clinical trial. Advanced age is not a contraindica-
thrombectomy was performed, or both, do the
following: tion to IV r-tPA, which should be offered to eligible patients
Admit patient to intensive care unit age 18 years or older. Relative contraindications to throm-
bolysis require the clinician to weigh the potential disability
Avoid invasive procedures (avoid use of indwelling
urinary catheter, nasogastric tubes, and intra- from the ischemic stroke and the degree of expected benefit
articular catheters for ≥4 h) from thrombolysis against the risk of hemorrhage and com-
Do not administer antiplatelet or anticoagulant plications. IV r-tPA treatment of patients in the clinical set-
medications for 24 h ting of relative contraindications should be individualized.
Frequently check vital signs (goal BP <185/110 mm The most feared complication of IV thrombolysis, which
Hg) and neurologic status should be discussed with the patient if possible, is symp-
tomatic intracerebral hemorrhage. The overall risk of symp-
Abbreviations: BP, blood pressure; h, hour; IV, intravenous;
tomatic intracerebral hemorrhage is approximately 6% with
NPO, nothing by mouth.
IV r-tPA administration. However, in the clinical studies that
established its use, the 90-day mortality rate did not differ
between the treated and the untreated patients. Thrombolysis
treatment carries a 12% absolute increased likelihood of

lesion, large infarction). Good practice guidelines recom-
functional independence.
mend completing the CT of the brain within 25 minutes and
IV r-tPA use is associated with a 12% absolute increased
interpreting the results within 45 minutes of patient arrival.
likelihood of functional independence.
Emerging data on tenecteplase, a more fibrin-specific
thrombolytic, suggest efficacy in stroke and has the advan-
Treatment Options for Acute Stroke tage of a single bolus.
Intravenous Thrombolysis
Administration of IV r-tPA
All patients for whom an ischemic stroke is suspected who Good practice guidelines suggest that door-to-needle times
present with disabling focal neurologic deficits within 3 for IV r-tPA administration be less than 60 minutes from
hours of symptom onset or last known well and have no patient arrival to the emergency department in at least 50%
contraindication to systemic IV thrombolysis should be of cases. The dose of IV r-tPA is 0.9 mg/kg, to a maximum
offered treatment with IV recombinant tissue plasminogen of 90 mg. The first 10% of the total dose is administered as
activator (r-tPA), which is approved by the US Food and an IV bolus over 1 minute; the other 90% should then be
Drug Administration (FDA) for this indication. infused over 1 hour. The patient should be monitored for
Table 50.1 • National Institutes of Health Stroke Scale (Condensed Version)
Instruction Definition Score
Level of consciousness Alert 0

Drowsy 1
Stuporous 2
Coma 3
Level of consciousness questions Answers both correctly 0
Answers 1 correctly 1
Answers neither correctly 2
Level of consciousness commands Obeys both correctly 0
Obeys 1 correctly 1
Obeys neither correctly 2
Best gaze Normal 0
Partial gaze palsy 1
Forced deviation 2
Visual No visual loss 0
Partial hemianopia 1
Complete hemianopia 2
Bilateral hemianopia 3
Facial palsy Normal facial movement 0
Minor paresis 1
Partial paresis 2
Complete palsy 3
Motor arm—left arm No drift 0
Drift 1
Some effort against gravity 2
No effort against gravity 3
No movement 4
Motor arm—right arm No drift 0
Drift 1
No movement 4
Motor leg—left leg No drift 0
Drift 1
No movement 4
Motor leg—right leg No drift 0
Drift 1
No movement 4
Limb ataxia Absent 0

Present in 1 limb 1
Present in 2 limbs 2
Sensory Normal 0
Partial loss 1
Dense loss 2
Best language No aphasia 0
Mild-to-moderate aphasia 1
Severe aphasia 2
Mute 3
Dysarthria Normal articulation 0
Mild-to-moderate slurring 1
Severe and nearly unintelligible or worse 2
Extinction and inattention No neglect 0
Partial neglect 1
Profound neglect 2
Modified from NIH Stroke Scale (Internet). Bethesda (MD): National Institutes of Health; National Institute of Neurological
Disorders and Stroke. c2003 (cited 2019 Sep 20). Available from: https://stroke.nih.gov/resources/scale.htm.
Orolingual angioedema is a rare acute complication of

Box 50.2 • Absolute and Relative Contraindications IV r-tPA administration. When it occurs, the r-tPA therapy
for the Use of Intravenous Thrombolytics must be stopped. The patient may require endotracheal
intubation if airway edema and respiratory distress
Absolute contraindications
evolves. IV methylprednisolone should be administered at
Acute intracranial hemorrhage
125 mg and diphenhydramine at 50 mg, and subcutaneous
Subarachnoid hemorrhage epinephrine injection should be considered. Alternative
CT imaging of the brain showing extensive regions of antihistamines include ranitidine and famotidine.
acute infarction
Thrombolysis- associated symptomatic intracerebral
Active internal bleeding hemorrhage is associated with neurologic deterioration
Gastrointestinal tract genitourinary malignancy or with or without headache and is a neurologic emergency.
bleeding within 21 d
The r-tPA therapy must be stopped and a non–contrast
Recent (within 3 mo) intracranial or intraspinal surgery medium head CT must be done immediately. Laboratory
Recent (within 3 mo) serious head trauma testing needs to be performed immediately for complete
History of intracranial hemorrhage blood cell count, measures of coagulation, fibrinogen level,
Presence of intra-axial neoplasm and type and cross match. If acute hemorrhage is present
Bleeding diathesis or coagulopathy on the head CT, 10 U of cryoprecipitate should be admin-
Platelet count <100×103/μL istered; if the fibrinogen concentration is less than 200 mg/
INR >1.7 dL, fibrinogen should be administered. The antifibrinol-
aPTT >40 s ytic compounds tranexamic acid or aminocaproic acid
may also be infused. Immediate neurosurgical consulta-
PT >15 s
tion should be obtained for recommendations for surgical
Current severe, uncontrolled hypertension
>185/110 mm Hg despite treatment management.
Any focal neurologic deterioration or sudden headache
Direct oral anticoagulant use (thrombin inhibitors,
factor Xa inhibitors) <48 h from last dose should prompt concern for symptomatic intracerebral
Infective endocarditis hemorrhage, which is a neurologic emergency.
Aortic arch dissection
Endovascular Therapy
Relative contraindications For the acute ischemic stroke of a patient presenting with a
Early improvement thrombotic occlusion of a large intracranial vessel, an excel-
Preexisting disability (mRS >2) or cognitive deficit lent therapeutic choice is endovascular therapy (EVT) with
Seizure at onset catheter-based, stent-
assisted, mechanical clot retrieval.
Blood glucose <50 mg/dL or >400 mg/dL (should be This clot retrieval should be performed under the appropri-
corrected) ate clinical circumstances. The procedure is termed
Dural puncture in the preceding 7 d mechanical thrombectomy and is performed with a stent-
Arterial puncture at a noncompressible site in the based retriever device or clot aspiration, or both, under
preceding 7 d fluoroscopic guidance by a radiologist, neurosurgeon, or
Recent major trauma in the preceding 14 d that did not neurologist. High-level clinical trial evidence guides the
involve the head management of mechanical thrombectomy for occlusions
Recent major surgery in the preceding 14 d of the anterior circulation, including intracranial carotid
Intracranial arterial dissection terminus and first division of the middle cerebral artery.
Vascular malformation and unruptured or unsecured Large- vessel occlusions typically present with more
intracranial aneurysm >10 mm severe strokes, as indicated with a higher NIHSS score (ie,
>6), although exceptions exist. A stroke patient with a sus-
Abbreviations: aPTT, activated partial thromboplastin time; pected large-vessel occlusion should receive a noninva-
CT, computed tomography; d, day; h, hour; INR,
international normalized ratio; mo, month; mRS, modified sive vascular imaging study of the cervical and intracranial
Rankin scale; PT, prothrombin time; s, second. vasculature (commonly, CT angiography) to define the
presence of a thrombotic occlusion of the major intracra-
nial vessel as soon as possible. Often, this imaging can be
done in sequence with the initial head CT while eligibility
development of complications from IV r- tPA, which
for IV r-tPA therapy is being considered or as IV r-tPA is
include orolingual angioedema, systemic hemorrhage, and
administered.
intracranial hemorrhage.
Chapter 50. Acute Ischemic Stroke Evaluation and Treatment 415
EVT Eligibility EVT in the Period of 6 to 24 Hours

After a large-vessel occlusion has been defined radiograph- In highly selected circumstances, a mechanical thrombec-
ically in the distal internal carotid or proximal middle tomy can be performed in an extended time window of up
cerebral artery, the eligibility for mechanical thrombec- to 24 hours from symptom onset. The extended window
tomy is determined (Box 50.3). First, a measure of func- criteria for patient selection were derived from 2 recent
tional disability termed the modified Rankin scale (mRS) clinical trials—at 6 to 16 hours and 6 to 24 hours from
score is used to determine the prestroke functional status. symptom onset or last known well. Patients are selected for
A candidate for EVT should have a score of less than 2, an extended-window embolectomy either because of the
consistent with functional independence before the stroke. size and ratio of the ischemic penumbra of the stroke tissue
Second, the patient’s head CT should be assessed for the or the presence of a clinical imaging mismatch between the
presence of a disqualifying large region of acute infarction severity of the clinical deficit and the volume of the core
with use of the Alberta Stroke Program Early CT Score infarct (irreversibly dead tissue). Both the size of the isch-
(ASPECTS). ASPECTS is a 10-point scale used to deter- emic penumbra and the core infarct are determined
mine the degree of existing early ischemic changes in the through perfusion imaging either with CT perfusion or
distribution of the middle cerebral artery; 1 point is magnetic resonance diffusion-weighted imaging.
deducted for each region that shows early ischemic changes
(eg, CT hypodensity, loss of grey-white differentiation, sul- • Thrombolysis with IV r-tPA has FDA approval for the
cal effacement). A score of 10 indicates no early CT changes treatment of acute ischemic stroke within 3 hours of
of ischemia. An ideal candidate for EVT should have an symptom onset.
ASPECTS reading of 6 or more for minimization of the risk • IV r-tPA should be considered only for patients who do
of reperfusion hemorrhage (Figure 50.2). Third, the time not have an absolute contraindication.
from symptom onset to groin puncture should be less than • Before IV r-tPA, a non–contrast medium head CT is
6 hours. required.
• The risk of symptomatic intracerebral hemorrhage
with thrombolysis is approximately 6%.
• The presence of a large-vessel occlusion on a
Box 50.3 • Endovascular Therapy Eligibility
noninvasive vascular study should prompt
Standard <6-h window consideration for the possibility of endovascular
Prestroke modified Rankin score 0 or 1 therapy.
Occlusion of internal carotid artery or middle cerebral
• Patient selection for endovascular therapy depends on
artery segment premorbid functional status, degree of established
NIHSS score ≥6 infarction, and time from symptom onset.
ASPECTS ≥6
• In selected cases, EVT may be performed as late as
24 hours from symptom onset, but advance diagnostic
Groin puncture can be initiated within 6 h from
symptom onset neuroimaging of the core infarct and ischemic
penumbra is necessary to select these patients.
Age ≥18 y
• Before endovascular therapy in the 6-hour window, a
6-to 16-h extended window embolectomy (DEFUSE 3
criteria) non–contrast medium head CT and CTA head and
neck or magnetic resonance imaging (MRI) with vessel
Infarct core <70 cc
imaging are required.

Penumbra to core ratio >1.8
• Before endovascular therapy in the 6-to 24-hour
Penumbra >15 cc
window, either non–contrast agent head CT, CTA head
6-to 24-h extended window embolectomy (DAWN and neck, and CT perfusion or non–contrast agent CT,
criteria)
brain MRI, and vessel imaging are required.
Age <80 y, infarct core 0-21 cc, and NIHSS ≥10
Age <80 y, infarct core 31-51 cc, and NIHSS ≥20
Age >80 y, infarct core 0-21 cc, and NIHSS ≥10
Posttreatment Guidelines
Abbreviations: ASPECTS, Alberta Stroke Program Early
Both medical and interventional management of acute
Computed Tomography Score; cc, cubic centimeter; DAWN,
Clinical Mismatch in the Triage of Wake Up and Late ischemic stroke happens within the first hours after
Presenting Strokes Undergoing Neurointervention With Trevo; patient arrival to the emergency department. A patient
DEFUSE 3, Endovascular Therapy Following Imaging
receiving either IV thrombolysis or mechanical throm-
Evaluation for Ischemic Stroke; h, hour; NIHSS, National
Institutes of Health Stroke Scale; y, year. bectomy should be admitted to a neurosciences inten-
sive care unit that has expertise in poststroke
A B
M1
M4
C
I L
M2
IC M5
M3 M6
Figure 50.2 Alberta Stroke Program Early Computed Tomography (CT) Score (ASPECTS). ASPECTS subdivides the
distribution of the middle cerebral artery into 10 regions. Beginning with a score of 10, a point is deducted for each region
that shows early ischemic change. This head CT has an ASPECTS of 10. A, Ganglionic level. C indicates caudate head; I,
insular cortex; IC, internal capsule; L, lentiform nuclei; M1, frontal operculum; M2, anterior temporal lobe; M3, posterior
temporal lobe. B, Supraganglionic level. M4 indicates anterior middle cerebral artery; M5, frontal lobe; M6, posterior middle
cerebral artery.
management. Large posterior fossa infarctions or hemi- Conclusion

spheric infarctions may also require care at an intensive
care unit. Symptomatic cerebral edema typically peaks An acute ischemic stroke is difficult to predict and is
clinically between day 3 and day 5 and may require potentially lethal. Treatment requires rapid mobilization of
hypertonic saline or mannitol management. Symptomatic substantial resources. Currently, the area of acute stroke
cerebral edema secondary to infarction or hemorrhagic management can offer considerable benefit to a patient.
transformation may result in neurologic deterioration, The successful treatment of an acute ischemic stroke may
thereby requiring neurosurgical intervention (see the result in functional independence after the hospitalization
discussion of hemicraniectomy in Chapter 56, “Principles and should be the goal of each stroke code. Ultimately, suc-
and Management of Alterations in Intracranial Pressure”). cessfully treated acute ischemic strokes can result from an
The patient who does not receive IV r-tPA or EVT and interdisciplinary team of experts working together for the
does not have a serious risk of swelling and is otherwise good of the patient. The criteria for endovascular treatment
clinically stable may be admitted directly to a dedicated is a rapidly evolving area of research. Ongoing trials are
stroke floor for continued care. assessing direct to endovascular therapy bypassing throm-
bolytics and assessing newer stent retrievers.
Secondary Prevention of Ischemic Stroke
51 LINDSY N. WILLIAMS, MD
Introduction to 30 days. However, long-term use is generally not recom-

mended for secondary stroke prevention unless the patient
A
fter an ischemic stroke is diagnosed, a diagnostic has another indication, such as a cardiac drug- eluting
evaluation ensues to determine the mechanism of stent. Dual antiplatelet therapy for the short term may also
the stroke and contributing risk factors. (See be considered for patients with large-vessel intracranial
Chapter 48, “Ischemic Stroke: Common Causes and stenosis. Several clinical trials have shown that long-term
Diagnosis.”) The appropriate antithrombotic is selected in (>90 days) dual antiplatelet therapy for stroke (aspirin in
accordance with the mechanism of the stroke, and the con- combination with clopidogrel) is not more effective and
tributing risk factors are treated with pharmacologic agents carries a higher bleeding risk. Evolving data suggest simi-
and lifestyle changes. This chapter discusses the selection lar duration ticagrelor and aspirin as a possible alternative.
of antithrombotic medication, medical treatment, and life- No clinical trial has addressed therapy when a patient
style changes for contributing risk factors. Treatment of has a stroke while taking a specific antiplatelet agent. When
specific mechanisms of stroke is also covered in Chapter antiplatelet therapy fails, options include 1) determining
48, “Ischemic Stroke: Common Causes and Diagnosis.” possible reasons for failure (Box 51.2), 2) searching for a
mechanism that requires an alternative to an antiplatelet
agent, and 3) switching to an alternative antiplatelet agent.
Antithrombotic Therapy In addition to consideration of the antiplatelet agent, other
Antiplatelet Management vascular risk factors should be assessed and modified.
All patients with ischemic stroke or transient ischemic Anticoagulant Management for Atrial Fibrillation
attack (TIA) should receive a prescription of antiplatelet
therapy for secondary prevention of recurrent stroke unless Atrial fibrillation is an important risk factor for stroke that
should be assessed and treated aggressively to reduce the
an indication exists for anticoagulation (Box 51.1) or other

intervention. Appropriate options are aspirin (50-325 mg), risk of recurrent ischemic stroke. Multiple randomized
aspirin (25 mg) in combination with extended- release clinical trials have shown that anticoagulation is superior
dipyridamole (200 mg), and clopidogrel (75 mg). Selection to single antiplatelet therapy or dual antiplatelet therapy in
may be individualized according to cost, other medica- prevention of cerebral ischemia for high-risk patients with
tions, tolerances, and clinical circumstances. atrial fibrillation. The risk can be assessed with the score
Recent studies have indicated that short-term use of from CHADS2 (congestive heart failure, hypertension, age
aspirin in combination with clopidogrel may be beneficial ≥75 years, diabetes mellitus, and stroke/TIA symptoms pre-
immediately after a small stroke or TIA and for the first 21 viously) or CHA2DS2-VASc (congestive heart failure,
Abbreviations: CHADS2, congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, and prior stroke or transient
ischemic attack; CHA2DS2-VASc, congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, stroke or transient isch-
emic attack or thromboembolism, vascular disease, age 65 to 74 years, and sex category (female); DOAC, direct oral anticoagulant; HbA1c,
hemoglobin A1c; PCSK-9, proprotein convertase subtilisin/kexin type 9; TIA, transient ischemic attack
417
Box 51.1 • Indications for Antiplatelet or Table 51.1 • CHA2DS2-VASc Score

Anticoagulation Agents for Patients With Ischemic CHA2DS2-VASc Components Points
Strokea
Congestive heart failure/left ventricular dysfunction 1
Hypertension 1
Indications for antiplatelet agent
Age ≥75 y 2
Large-vessel stenosis (extracranial or intracranial)
Diabetes mellitus 1
Small-vessel disease or lacunar stroke
Stroke/TIA/thromboembolism 2
Cryptogenic strokeb
Vascular disease (prior MI, PVD, or aortic plaque) 1
Indications for anticoagulation Age 65-74 y 1
Atrial fibrillation Sex category (ie, female gender) 1
Mechanical heart valve Abbreviations: MI, myocardial infarction; PVD, peripheral vascular
Left ventricular or left atrial thrombus disease; TIA, transient ischemic attack.
Phospholipid antibody syndrome From Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining
clinical risk stratification for predicting stroke and thromboembolism
a
Areas of controversy for antithrombotic selection are arterial in atrial fibrillation using a novel risk factor-based approach: the euro
dissection and dilated cardiomyopathy. heart survey on atrial fibrillation. Chest. 2010 Feb;137(2):263-72.
Epub 2009 Sep 17; used with permission.
b
Best treatment (antiplatelet with direct oral anticoagulant) for
a type of cryptogenic stroke referred to as embolic strokes
of undetermined source is currently a topic of controversy
and a source of ongoing investigation. For valvular atrial fibrillation, warfarin is indicated,
with a goal international normalized ratio of 2 to 3. In non-
valvular atrial fibrillation, choices include warfarin or a
hypertension, age ≥75 years, diabetes mellitus, stroke or direct oral anticoagulant (DOAC). The DOACs include
TIA or thromboembolism, vascular disease, age 65-74 dabigatran, rivaroxaban, edoxaban, and apixaban (Table
years, and sex category [female]) (Table 51.1 and Table 51.3). The choice on which agent to use may depend on
51.2). In general, a CHA2DS2-VASc score of 2 or higher war- various factors, including kidney function, weight, bleed-
rants anticoagulation. ing risk, ability to comply with medication regimens, abil-
If no contraindications exist, patients with both cere- ity to comply with diet (warfarin), ability to monitor
bral ischemia and atrial fibrillation should begin oral anti- medication, and cost. A comparison of these agents with a
coagulation therapy after computed tomography or vitamin K antagonist in clinical trials of patients with
magnetic resonance imaging of the brain has excluded atrial fibrillation is provided in Table 51.4. For patients
intracranial hemorrhage or large infarct. The timing of who have received a prescription for DOACs, renal
anticoagulation depends on whether intravenous tissue
plasminogen activator was administered (ie, must wait 24
hours after administration), on the size of the infarction, Table 51.2 • Interpretation of CHA2DS2-VASc Score and
and therefore on the risk of hemorrhagic conversion. Annual Risk of Stroke
Score Thromboembolism Rate, % (95% CI)
Box 51.2 • Reasons for Failure of Antiplatelet 0 0.0 (0.0-0.0)

Therapy 1 0.6 (0.0-3.4)
2 1.6 (0.3-4.7)
Nonadherence to drug therapy
3 3.9 (1.7-7.6)
Concomitant use of NSAIDs or COX-2 inhibitors with
aspirin 4 1.9 (0.5-4.9)
Poor absorption 5 3.2 (0.7-9.0)
Impaired metabolism of clopidogrel (concomitant use
Abbreviation: CHA2DS2-VASc, congestive heart failure, hypertension, age 75
with proton pump inhibitors or other medications; years or older, diabetes mellitus, stroke or transient ischemic attack or
genetically poor metabolizer [CYP2C19]) thromboembolism, vascular disease, age 65 to 74 years, and sex category
Poor response (resistance) (female).
Data from Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining
Abbreviations: COX-2, cyclooxygenase 2; CYP2C19, clinical risk stratification for predicting stroke and thromboembolism
cytochrome P450 2C19 isozyme gene; NSAID, nonsteroidal in atrial fibrillation using a novel risk factor-based approach: the euro
anti-inflammatory drug. heart survey on atrial fibrillation. Chest. 2010 Feb;137(2):263-72.
Epub 2009 Sep 17.
Chapter 51. Secondary Prevention of Ischemic Stroke 419
Table 51.3 • Characteristics of the Direct Oral Anticoagulants

Anticoagulant
Characteristic Dabigatran Rivaroxaban Apixaban Edoxaban
Renal clearance, % 80 35 25 50
Enteric excretion − – + +
Bioavailability (%) pH dependent (6–7) Food dependent (66–90) Food independent (50) Food independent (62)
Liver CYP3A4 metabolism – + –/+ –/+
Effect of P-glycoprotein + + + +
transport system
Reversal agent Idarucizumab Andexanet alfa Andexanet alfa Andexanet alfa
function should be routinely monitored. For patients with requires temporary anticoagulation post procedure, fol-
atrial fibrillation, it is not recommended to combine aspi- lowed by daily aspirin. Candidacy for this treatment
rin with anticoagulation, unless the patient has an addi- should be reviewed by a neurologist and a cardiologist
tional indication such as coronary artery disease, because well versed in this treatment option.
of the bleeding risk.
For patients with atrial fibrillation who are not candi- • Multiple randomized clinical trials have shown that
dates for long-term anticoagulation because of increased anticoagulation is superior to antiplatelet agents in
bleeding risk, left atrial appendage closure may be an alter- preventing recurrent cerebral ischemia in patients with
native consideration. Percutaneous left atrial appendage atrial fibrillation.
closure has been shown effective in stroke reduction for • DOACs require at least annual renal function
patients with nonvalvular atrial fibrillation. This treatment assessment.
Table 51.4 • Comparison of Clinical Trials of the DOACs vs Vitamin K Antagonists

Trial (Medication), Dosesa
RE-LY ROCKET AF ARISTOTLE ENGAGE AF
(Dabigatran) (Rivaroxaban) (Apixaban) (Edoxaban)
110 mg 20 mg 5 mg 30 mg
Drug vs Vitamin K Antagonist 150 mg 60 mg
Ischemic strokeb ↔ ↔ ↔ ↑
↓ ↔
Hemorrhagic stroke ↓ ↓ ↓ ↓
↓ ↓
Major bleed ↓ ↔ ↓ ↓
↔ ↓
Intracranial bleed ↓ ↓ ↓ ↓
↓ ↓
GI tract bleed ↔ ↑ ↔ ↓
↑ ↑
All-cause death ↔ ↔ ↓ ↓
↓ ↔
Abbreviations: ARISTOTLE, Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; DOAC, direct oral anticoagulant;
ENGAGE AF, Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation; GI, gastrointestinal; RE-LY, Randomization Evaluation
of Long-term Anticoagulant Therapy; ROCKET AF, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism
for Prevention of Stroke and Embolism Trial in Atrial Fibrillation.
a
The horizontal (sideways) arrow indicates no difference compared with warfarin; downward arrow, DOAC reduces the indicated item compared with
warfarin; upward arrow, DOAC increases the indicated item compared with warfarin.
b
In columns where 2 arrows are shown, the top arrow refers to the lower dose in the column heading; the bottom arrow, the higher dose.
Medical Management hemoglobin A1c (HbA1c) level may be a more accurate

marker than fasting glucose concentration. Glycemic tar-
Blood Pressure Management gets should be individualized, although most patients may
Hypertension is the single most important modifiable risk benefit from achieving a glycated HbA1c level of 7.0%
factor for stroke. Lowering the systolic blood pressure by or less.
as little as 10 mm Hg and the diastolic blood pressure as
little as 5 mm Hg can reduce the relative risk of recurrent • Patients who have had a stroke or TIA should
stroke by about 25%. Blood pressure should be assessed, receive treatment to decrease their blood pressure
monitored, and managed for all patients with stroke to in the chronic phase, to achieve a target goal of
prevent recurrent stroke. Some patients may benefit ini- <130/80 mm Hg.
tially from permissive hypertension in the acute phase. • Patients with stroke or TIA due to atherosclerotic
The optimal time to treat hypertension following a stroke disease should receive high-intensity statin therapy.
is unknown and likely varies greatly depending on spe- • Patients with TIA or stroke should be screened for
cific patient characteristics. However, initiation of a treat- diabetes mellitus (with consideration of HbA1c in the
ment plan is reasonable before the patient’s dismissal from immediate post stroke period).
the hospital.
The 2017 American College of Cardiology/ American
Heart Association blood pressure guidelines recommend a Lifestyle Changes
goal blood pressure of less than 130/80 mm Hg for patients
In addition to pharmacologic therapy, patients should be
with cardiovascular disease or who have a 10% 10-year
counseled on lifestyle changes for stroke prevention. Some
risk of cardiovascular disease.
patients may benefit from a structured assessment and risk
factor management program. Lifestyle modification recom-
Lipid Management
mendations include the following:
The Stroke Prevention by Aggressive Reduction in Cholesterol
Levels trial randomly assigned patients without coronary • Diet: Mediterranean-style diet (fruits, vegetables, whole
artery disease and non-cardioembolic stroke to receive either grains, fish, legumes, plant-based oils rather than
80 mg of atorvastatin or placebo. This was the first trial to animal fats). Sodium intake reduction to 1.5 g/day
show a reduction in the risk of recurrent ischemic stroke in • Exercise: Three or four 40-minute sessions of moderate
addition to a reduction in myocardial infarction. to intense exercise per week. If appropriate,
Patients with ischemic stroke or TIA should have their consideration of consultation with physiatrist or
serum lipid levels assessed and managed. Therapeutic life- cardiac rehabilitation specialist
style changes, in addition to use of a statin, may be consid- • Tobacco: Tobacco cessation with counseling or
ered. High-intensity statin therapy should be considered pharmacologic management, or both, when
in secondary prevention for patients who have had isch- appropriate
emic stroke or TIA of atherosclerotic origin or who have a • Alcohol: Moderation of use (men, <2 drinks/day;
history of coronary artery disease. This high- intensity women, <1 drink/day)
statin therapy includes a 40-to 80-mg dose of atorvastatin • Hormone therapy: No estrogen-containing medications
daily and a 20-mg dose of rosuvastatin daily. Moderate- • Sleep: Evaluation and treatment of sleep apnea
intensity statin therapy is recommended for patients older

than 75 years or patients who have a high risk of statin-
related complications. If a patient does not reach a low- Asymptomatic Internal Carotid Artery
density lipoprotein cholesterol goal of less than 70 mg/dL
with moderate-to high-intensity statin therapy, ezetimibe
Stenosis
can be added or a proprotein convertase subtilisin/kexin Asymptomatic internal carotid artery stenosis increases
type 9 (PCSK-9) inhibitor can be considered, or both. For a the risk of ischemic stroke. Patients with a stenosis greater
patient with nonatherosclerotic stroke, the decision to use than 60% and no symptoms related to the internal carotid
statins depends on the patient’s 10-year risk of cardiovas- artery have an ipsilateral risk of ischemic stroke of approx-
cular disease, which can be calculated with the American imately 2% to 3% annually, based on trials predating the
College of Cardiology Calculator. widespread use of statins and tightened blood pressure
goals. This risk can be reduced to 1% annually with inter-
Diabetes Management vention (carotid endarterectomy or angioplasty and stent-
Patients with ischemic stroke or TIA should be screened ing). However, intervention carries a risk of ischemic stroke
for diabetes mellitus. Immediately following a stroke, of approximately 1.5% to 3%. Current estimates cite the
Chapter 51. Secondary Prevention of Ischemic Stroke 421
risk of ipsilateral stroke with antiplatelet therapy and indicated to reduce the risk of ischemic stroke. Ongoing
improved risk factor control is closer to 1.0% to 1.5% per studies are underway to determine whether the superior
year. Thus, considerable controversy has occurred about treatment is surgical management or medical management
intervention in this group of patients because the risk to for these patients.
benefit ratio is small. Antiplatelet therapy and statins are
Intraparenchymal Cerebral Hemorrhagea
52 MARIA I. AGUILAR, MD
Introduction use accounts for 15% to 17% of ICH cases. Less common
causes include other coagulopathies, hemorrhagic infarcts,
I
ntraparenchymal cerebral hemorrhage (ICH) is the hemorrhagic brain tumors, vascular malformations, and
presence of blood in the brain parenchyma. It is a neu- reversible cerebral vasoconstriction syndrome.
rologic emergency and may carry severe morbidity and Hypertensive ICH usually occurs in deep areas of the
death. The broad differential of ICH is presented in Box brain, such as basal ganglia, pons, and cerebellum (Figure
52.1. This chapter focuses mainly on spontaneous, non- 52.2). The underlying mechanism is the accelerated age-
traumatic ICH (ie, hemorrhage not related to trauma, arte- related degeneration of cerebral arterioles at their branch
riovenous malformation, cerebral aneurysm, or tumor). points.
In CAA, deposition of amyloid protein occurs in the
media and adventitia of arteries and arterioles, usually in
Epidemiologic and Etiologic Risk Factors the cerebral cortex (Figure 52.3). CAA leads to lobar hem-
orrhages, and recurrent lobar ICH is common in CAA.
Epidemiologic Factors
ICH accounts for 15% to 20% of all new strokes annually. • Intracerebral hemorrhage is twice as common as
Among the US general population, the incidence is 15 subarachnoid hemorrhage and just as deadly, with a
cases per 100,000 person-years. The incidence is highest 30-day mortality rate of 30%-50%.
among Asian populations (60 per 100,000 person-years), • The most common cause of intracerebral hemorrhage
followed in frequency by African Americans (30 per is hypertension (about 50% of cases), followed by
100,000 person-years). cerebral amyloid angiopathy (about 20%).
ICH is twice as common as subarachnoid hemorrhage • Hypertensive intracerebral hemorrhage usually occurs in
and just as deadly, with a 30-day mortality rate of 30% to deep areas of the brain, such as the basal ganglia, pons,
50%, which has not decreased since the early 2000s. The and cerebellum, whereas cerebral amyloid angiopathy
incidence and severity are likely to increase as the popula- tends to occur in the cortical or lobar regions.
tion ages.
Clinical Evaluation and Management
Causes
Clinical Presentation
The most common cause of ICH is hypertension (about
50% of cases), followed in frequency by cerebral amyloid Patients with ICH typically present with a sudden-onset,
angiopathy (CAA) (about 20%) (Figure 52.1). Anticoagulant focal neurologic deficit. Headache, impaired level of
a
Portions previously published in Han JH, Lee JM, Koh EJ, Choi HY. The spot sign predicts hematoma expansion, outcome, and mortality
in patients with primary intracerebral hemorrhage. J Korean Neurosurg Soc. 2014 Oct;56(4):303-9. Epub 2014 Oct 31; used under Creative
Common Attribution Non-Commercial License (https://creativecommons.org/ licenses/by-nc/3.0).
Abbreviations: CAA, cerebral amyloid angiopathy; CT, computed tomography; GRE, gradient-recall echo; ICH, intraparenchymal cerebral
hemorrhage; MRI, magnetic resonance imaging; SWI, susceptibility-weighted image
422
Chapter 52. Intraparenchymal Cerebral Hemorrhage 423
Box 52.1 • Differential Diagnosis of 50

Intraparenchymal Cerebral Hemorrhage
40
Hypertension—most commonly basal ganglia, internal
capsule, pons, cerebellum
Prevalence, %
Hypertensive vasculopathy, eclampsia
30
Cerebral amyloid angiopathy—commonly lobar; older
patients
Arteriovenous malformation 20
Cavernous malformation
Aneurysm rupture—can result in both subarachnoid
hemorrhage and intraparenchymal cerebral 10
hemorrhage
Moyamoya disease—typically basal ganglia
0
Vasculitis
Hypertension CAA Anticoagulation Other
Primary central nervous system tumor
Metastatic tumor—renal cell carcinoma, melanoma, Figure 52.1 Causes of Intraparenchymal Cerebral
lung cancer, choriocarcinoma
Hemorrhage. CAA indicates cerebral amyloid angiopathy.
Bleeding diathesis—low platelet count, disseminated
intravascular coagulation
Hemorrhagic conversion of ischemic stroke coagulopathies or systemic conditions that predispose to
Venous hypertension and infarction—typically cortical bleeding (eg, liver disease, hematologic malignancies).
Traumatic contusion—usually frontal pole and tip of Physical examination should include vital signs, a
temporal lobe general medical examination, level of consciousness
Medications—sympathomimetics, thrombolytic (Glasgow Coma Scale or Mayo Clinic Full Outline of
medication, warfarin Unresponsiveness score), and severity of neurologic defi-
cit (National Institutes of Health Stroke Scale).
Modified from Flemming KD. Principles of critical care
neurology. In: Mowzoon N, Flemming KD, editors. Neurology Routine laboratory studies should include complete
board review: an illustrated study guide. Rochester (MN): blood cell count, platelet count, determination of electro-
Mayo Clinic Scientific Press and Florence (KY): Informa lytes and renal function, coagulation profile (prothrombin
Healthcare USA; c2007. p. 401–34; used with permission of
Mayo Foundation for Medical Education and Research. time, partial thromboplastin time, and international nor-
malized ratio), toxicologic screen, and pregnancy test
when appropriate.
Non–contrast-agent computed tomography (CT) of the
consciousness, increased blood pressure, nausea, and eme-
head is considered the gold standard. Acute bleeding
sis are more common in ICH than in ischemic stroke.
appears hyperdense compared with the brain parenchyma
and similar to bone or contrast agent on CT scans win-
Diagnostic Evaluation
dowed to evaluate brain tissue. A fluid level in the hema-
Medical history should include time of symptom onset or toma or blood in different stages is suggestive of
of symptom awareness. A hematoma may expand in the coagulopathy (eg, warfarin-related ICH) (Figure 52.4).
initial 6 hours in noncoagulopathic ICH and in the initial If blood is seen on CT immediately after symptom onset,
24 hours in coagulopathy- related ICH. Perihematomal CT angiography and contrast-medium–enhanced CT may
edema and increased intracranial pressure reach maxi- be considered to help identify patients at risk for hematoma
mum levels around 72 hours after the ictus. expansion. A spot sign on post–contrast-medium CT is due
Associated activities at the onset might help identify the to a vascular leak at the point of enhancement and may
cause (eg, onset during coitus or physical activity is sugges- predict hematoma enlargement (Figure 52.5).
tive of rupture of a vascular structure, such as aneurysm or Magnetic resonance imaging (MRI) is useful to rule out
arteriovenous malformation). Additional medical history underlying structural abnormalities, such as tumors or arte-
should include recent head trauma, vascular risk factors riovenous malformations. The appearance of blood on MRI
(hypertension, diabetes mellitus, dyslipidemia, chronic depends primarily on the age of the hematoma and the type
kidney disease, tobacco use, and alcohol use), medications of MRI sequence (Table 52.1). In addition, MRI may show
(in particular, antithrombotic agents), history of both isch- alternative areas of microbleeds on gradient- recall echo
emic stroke and hemorrhagic stroke, and history of (GRE) imaging or susceptibility-weighted images (SWIs).
A B
C
Figure 52.2 Hypertensive Intraparenchymal Cerebral Hemorrhage on Non–Contrast-Medium Computed Tomography. A,

Right thalamus with intraventricular extension. B, Pons. C, Left putamen and globus pallidus with extension superiorly.
A B
Figure 52.3 Cerebral Amyloid Angiopathy (CAA). A, Computed tomography of intraparenchymal cerebral hemorrhage
(ICH) secondary to CAA shows right posterior frontal hematoma (image on left) and right temporal lobar intraparenchymal
hematoma (image on right). B, Cortical and leptomeningeal amyloid deposits are best shown with β-amyloid
immunohistochemistry. Of note, extensive β-amyloid deposition in the media and adventitia of the leptomeningeal arteries
and arterioles is apparent. C, Micrograph of ICH due to CAA shows patchy, confluent microhemorrhagic areas around an
arteriole (hematoxylin-eosin).
(B and C, From Flemming KD. Principles of critical care neurology. In: Mowzoon N, Flemming KD, editors. Neurology board review: an
illustrated study guide. Rochester [MN]: Mayo Clinic Scientific Press and Florence [KY]: Informa Healthcare USA; c2007. p. 401-34; used
with permission of Mayo Foundation for Medical Education and Research.)
Microbleeds or microhemorrhages are small areas (<10 Rarely, melanoma or myxomatous emboli have a similar
mm) of ferritin and hemosiderin deposition that appear as appearance. The location and clinical context of the
signal dropout (profoundly hypointense) on hemosiderin- microbleeds are important in determining the poten-
sensitive sequences. These are considered the radiologic tial cause.
footprint of CAA when diffuse and predominantly in a Conventional angiography is indicated for patients who
cortical or subcortical location. When microbleeds are have an atypical clinical or radiologic presentation (eg,
located in the basal ganglia, brainstem, or cerebellum of calcification in the hematoma), when another cause is not
patients who have evidence of microvascular white mat- found, or when subarachnoid hemorrhage associated with
ter disease or lacunar stroke (or both), they are likely part ICH is present without associated head trauma.
of the spectrum of small-vessel cerebrovascular disease
(Figure 52.6). However, the differential diagnosis of these Management
hypodense areas on GRE or SWIs includes CAA, hyper-
tensive microbleeds, multiple cavernous malformations, After the diagnosis of ICH has been established, supportive
calcium, trauma, and mechanical heart valve emboli. measures are initiated. Airway, breathing, and circulation
are assessed, and the patient is intubated if needed. A tar-

get serum glucose level of 140 to 185 mg/dL should be
obtained. According to the 2015 American Stroke
Association guidelines, for a patient who presents with a
systolic blood pressure of 150 to 220 mm Hg and without
contraindication to acute blood pressure treatment, acute
lowering of systolic blood pressure to 140 mm Hg is safe
and can improve functional outcome.
Corticosteroids and prophylactic anticonvulsants are
not recommended in ICH. Therapy with antithrombotic
agents should be discontinued and any coagulopathies
corrected. Noncoagulopathic ICH is not an indication for
treatment with blood products or with recombinant factor
VIIa. For warfarin-related ICH, treatment recommenda-
tions based on suboptimal evidence are to give vitamin K
(10 mg as a slow intravenous infusion over 30 minutes),
fresh frozen plasma (initial dose, 10-15 mL/kg), and 3-or
4-factor prothrombin complex concentrate or, in an off-
label use, recombinant factor VIIa (40 mcg/ kg intrave-
nously, rounding up to the nearest 1.2-mg vial size).
Idarucizumab can be used to reverse the effects of dabi-
gatran. Andexanet alpha was approved in early 2018 to
revert coagulopathy due to the use of rivaroxaban or apixa-
ban, or both.
Figure 52.4 Computed Tomography of Heterogeneous Left For most patients with ICH, the usefulness of surgery is
Occipital Intraparenchymal Cerebral Hemorrhage With uncertain. Patients with cerebellar hemorrhage and a dete-
Fluid Levels and Blood in Different Stages. The patient was riorating neurologic status or who have brainstem com-
receiving warfarin therapy. The international normalized pression or hydrocephalus (or both) from ventricular
ratio was 4.2. obstruction should undergo surgical removal of the hemor-
rhage as soon as possible. For patients presenting with
lobar hemorrhages larger than 30 cm3 and within 1 cm of
A B C D
Figure 52.5 Spot Sign, Extravasation, and Hematoma Expansion on Computed Tomography (CT). CT slice selection has
been optimized for hematoma configuration, not for head position. A, Unenhanced CT shows left posterior putaminal and
internal capsule hematoma with mild surrounding edema. An old parietooccipital infarct is seen posterior to this. B, A
small focus of enhancement is seen peripherally on CT angiography source images, consistent with the spot sign (arrow). C,
Post–contrast-agent CT shows enlargement of the spot sign, consistent with extravasation (arrow). D, Unenhanced CT image
1 day after presentation shows hematoma enlargement and intraventricular hemorrhage.
(From Wada R, Aviv RI, Fox AJ, Sahlas DJ, Gladstone DJ, Tomlinson G, et al. CT angiography “spot sign” predicts hematoma expansion
in acute intracerebral hemorrhage. Stroke. 2007 Apr;38[4]‌:1257-62. Epub 2007 Feb 22; used with permission.)
Table 52.1 • Magnetic Resonance Imaging Characteristics of Intraparenchymal Cerebral

Hemorrhage
Signala and Area of Hemorrhage
T1 Signal T2 Signal
Stage Timing Central Peripheral Central Peripheral
Hyperacute <12 h ↔ ↔ ↑ ↑
Acute 12–72 h ↔ ↔ ↓ ↑
Early subacute 4–7 d ↔ ↑ ↓ or ↔ ↓↓
Late subacute 1–4 wk ↑↑ ↑↑ ↑↑ ↑↑
Chronic Months ↑ ↓ ↑ ↓
Late chronic Months to years ↓↓ ↓↓ ↑ ↓↓

a
Arrows indicate the following: ↓, decreased; ↓↓, markedly decreased; ↑, increased; ↑↑, markedly increased;
and ↔, isodense.
Modified from Flemming KD. Principles of critical care neurology. In: Mowzoon N, Flemming KD, editors. Neurology
board review: an illustrated study guide. Rochester (MN): Mayo Clinic Scientific Press and Florence (KY): Informa
Healthcare USA; c2007. p. 401-34; used with permission of Mayo Foundation for Medical Education and Research.
A B
Figure 52.6 Microbleeds. A, This patient had uncontrolled chronic hypertension and microbleeds that affected the basal
ganglia and were apparent on T2*-weighted gradient-echotomographic magnetic resonance imaging. B, An 85-year-old
patient had dementia, presumed cerebral amyloid angiopathy, diffuse cortical and subcortical microbleeds, and recurrent
lobar intraparenchymal cerebral hemorrhage.
for patients with lack of mobility, at 3 or 4 days after

Table 52.2 • Determination of the ICH Score
the ictus.
Component ICH Score Points
GCS scorea • A spot sign on post–contrast-medium CT is due to a

3–4 2 vascular leak at the point of enhancement and may
5–12 1 predict hematoma enlargement.
13–15 0 • MRI is useful to rule out underlying structural
ICH volume, cm3 abnormalities, such as tumors or arteriovenous
≥30 1 malformations.
<30 0 • Microbleeds or microhemorrhages are small areas (<10
IVH mm) of ferritin and hemosiderin deposition appearing
Yes 1 as signal dropout (profoundly hypointense) on T2
No 0
gradient-echotomographic images. The location of
Infratentorial origin of ICH these, when present, may indicate hypertensive (deep)
Yes 1 or cerebral amyloid (lobar) angiopathy causes.
No 0
However, the differential diagnosis is broad.
Age, y • Corticosteroids and prophylactic anticonvulsants are
≥80 1
not used in typical ICH.
<80 0
• For most patients with ICH, the usefulness of surgery
Abbreviations: GCS, Glascow Coma Scale; ICH, intracerebral is uncertain.
hemorrhage; IVH, intraventricular hemorrhage.
a
GCS score indicates GCS score on initial presentation (or after
resuscitation); ICH volume, volume on initial computed tomography
(CT) calculated using ABC/2 method; and IVH, presence of any IVH
on initial CT. Outcome
From Hemphill JC 3rd, Bonovich DC, Besmertis L, Manley GT, Johnston
SC. The ICH score: a simple, reliable grading scale for intracerebral The overall mortality rate of patients with ICH is 30% to
hemorrhage. Stroke. 2001 Apr;32(4):891-7; used with permission. 40% at 30 days and 50% at 1 year. The ICH score is a sim-
ple, easy clinical grading scale for risk stratification of
the surface, evacuation of the supratentorial hemorrhage patients at presentation (Table 52.2). The 30-day mortality
by standard craniotomy may be considered. rate based on the number of points in the ICH score is 0%
The effectiveness of minimally invasive hemorrhage (0 points), 13% (1 point), 26% (2 points), 72% (3 points),
evacuation by stereotactic or endoscopic aspiration with 97% (4 points), and 100% (5 or 6 points).
or without thrombolysis is uncertain and an area of ongo- The best predictor of clinical outcome is hematoma vol-
ing investigation. ume at presentation. Hematoma volume is calculated as
A reasonable approach is to provide aggressive, full (A×B×C)/2, where A is the maximum ICH diameter (cm), B
care early after ICH onset and to postpone new do-not- is the maximum ICH diameter (cm) perpendicular to A,
resuscitate orders until at least the second full day of hos- and C is the maximum vertical diameter (cm). Typically,
pitalization. After the bleeding has been stopped and the the CT slice thickness is 0.4 to 0.5 cm.
cessation documented, low- dose subcutaneous low-
molecular-weight heparin or unfractionated heparin may • The ICH score is a simple, easy clinical grading scale
be considered for prevention of venous thromboembolism for predicting 30-day mortality rate.
Unruptured Intracranial Aneurysms and
53 Vascular Malformationsa
ROBERT D. BROWN JR, MD, MPH
Introduction year. About 85% of intracranial aneurysms occur anteri-

orly in the Circle of Willis, with common sites including
K
nowledge of the natural history of unruptured the internal carotid artery terminus, posterior communi-
intracranial aneurysms and vascular malforma- cating artery origin, anterior communicating artery to
tions of the brain is important because this infor- anterior cerebral artery junction, and proximal middle
mation can be weighed against the morbidity and death cerebral artery. Posteriorly, the most common locations
rates of intervention to decide on the most appropriate are the tip of the basilar artery and the superior cerebellar
treatment of an individual patient. This chapter reviews artery, anterior inferior cerebellar artery, and posterior
the epidemiologic factors and natural history of common inferior cerebellar artery junctions with the basilar artery
intracranial vascular abnormalities. (Figure 53.1).
Aneurysms occur more frequently in adult patients (age
>18 years) and are detected rarely in children. Aneurysms
Unruptured Intracranial Aneurysms occur much more often in women than in men (3:1 ratio). In
addition to age and female sex, risk factors for aneurysm devel-
Saccular Aneurysms opment include cigarette smoking, hypertension, selected
Epidemiologic Factors inherited conditions, and a family history of 2 or more first-
Intracranial saccular or berry aneurysms are acquired degree relatives having a brain aneurysm (Box 53.1).
lesions, accounting for about 80% of all nontraumatic sub-
arachnoid hemorrhages (SAHs). Most saccular aneurysms Aneurysm Screening
are detected before rupture and during imaging performed The overall occurrence of unruptured aneurysms is
for unrelated reasons. About 0.5% to 2% of the population increased in family members of patients with UIA. Among
has an unruptured intracranial saccular aneurysm (UIA), first-
degree relatives (siblings, parents, and children) of
and multiple aneurysms are detected in 20% to 30% of patients with a history of SAH, 4% have a UIA; siblings are
these patients. This percentage suggests that 3 million to 6 the most likely relatives to have an aneurysm detected. For
million people in the United States have an intracranial patients with 2 or more relatives who have a brain aneu-
aneurysm. The most feared complication is SAH, which rysm, the risk of UIA is about 9% for relatives older than 30
occurs in about 30,000 people in the United States each years. In families that have at least 2 members with brain
a
Portions previously published in Brown RD Jr, Flemming KD, Meyer FB, Cloft HJ, Pollock BE, Link ML. Natural history, evaluation, and
management of intracranial vascular malformations. Mayo Clin Proc. 2005 Feb;80(2):269-81; used with permission of Mayo Foundation
for Medical Education and Research.
Abbreviations: AVM, arteriovenous malformation; CCM, cerebral cavernous malformation; CT, computed tomography; CTA, computed
tomographic angiography; DVA, developmental venous anomaly; MRA, magnetic resonance angiography; MRI, magnetic resonance
imaging; NIA, nonsaccular intracranial aneurysm; SAH, subarachnoid hemorrhage; UIA, unruptured intracranial saccular aneurysm
429
Anterior Circulation Posterior Circulation
Anterior communicating artery

(30%-40%)
Middle cerebral artery

(20%-30%)
Vertebrobasilar
arterial system
Internal carotid artery (10%)
(30%)
(Note: This includes carotid
cavernous, ophthalmic, posterior
communicating, and anterior
choroidal segments)
JVH
© MAYO
2014
Figure 53.1 Common Locations of Intracranial Aneurysms. Percentages are approximate frequencies.
aneurysm, the frequency of detection of UIA is nearly 20% On computed tomography (CT) of the head without
among first-degree relatives who either smoke cigarettes or contrast medium or on magnetic resonance imaging (MRI)
have hypertension and are older than 30 years. Screening of the brain, a UIA may appear as a well-circumscribed
with computed tomographic angiography (CTA) or mag- structure that is slightly hyperintense, and it may have cal-
netic resonance angiography (MRA) is typically recom- cification in the wall. UIAs are more readily detected and
mended for the first- degree relatives of affected family assessed noninvasively with CTA or MRA (Figure 53.2).
members when there is a history of 2 or more family mem- Both techniques are sensitive for saccular aneurysms with
bers with SAH or brain aneurysm. Screening is optional for diameters of at least 4 mm. Cerebral arteriography may be
families with 1 known family member affected with SAH necessary for clarifying the details of the aneurysm and
or brain aneurysm. In families with autosomal dominant defining the optimal treatment strategy if endovascular or
polycystic kidney disease, screening is recommended for surgical treatment is being considered.
patients who have polycystic kidney disease and a family
history of aneurysm. Natural History
The risk of aneurysm rupture appears to depend on aneu-
Clinical Presentation rysm size, with larger aneurysms predictive of a higher risk
Some patients present with SAH, but many saccular aneu- of hemorrhage, and on aneurysm location, with posterior
rysms are detected in patients who have no symptoms. circulation and posterior communicating artery aneurysms
Besides SAH, UIA may result in local mass effect, commonly potentially associated with a higher risk of rupture than
a cranial nerve palsy such as an ipsilateral cranial nerve III anterior circulation. Anterior communicating artery loca-
compression due to an aneurysm of the posterior communi- tion has been variably associated with a higher risk of hem-
cating artery. Headaches and seizures occur uncommonly. orrhage. The risk of hemorrhage is also increased with
Transient ischemic attacks or cerebral infarction rarely occurs enlarging UIAs. The morphologic characteristics of aneu-
from distal embolization of thrombus within the aneurysm. rysms, such as the presence of a daughter sac, have been
Chapter 53. Unruptured Intracranial Aneurysms and Vascular Malformations 431
that the risk of complications was lower with aneurysm

Box 53.1 • Risk Factors and Genetic and Medical coiling.
Conditions Associated With Cerebral Aneurysm When UIAs are managed conservatively, annual follow-
Formation up imaging with CTA or MRA is typically recommended to
assess for aneurysm growth. The ELAPSS score may be
Risk factors for cerebral aneurysm formation
used to predict the likelihood of aneurysm growth. This
Age
score takes into account earlier subarachnoid hemorrhage,
Female sex aneurysm location, age, population, aneurysm size, and
Hypertension aneurysm shape.
Cigarette smoking
Predisposing genetic conditions for cerebral aneurysms Other Aneurysm Types
Autosomal dominant polycystic kidney disease
Infectious (Mycotic) Aneurysms
(prevalence, 10%)
Mycotic aneurysms are relatively uncommon; they make
Vascular type of Ehlers-Danlos syndrome (formerly
type IV) up about 3% of all intracranial aneurysms. Up to 12% of
patients with infectious endocarditis have an intracranial
Hereditary hemorrhagic telangiectasia (Osler-Weber-
Rendu disease) aneurysm, which results from septic emboli that either
Neurofibromatosis type 1 infect the intima and cause inflammation of the muscularis
or lodge in the vasa vasorum and cause destruction of the
Pseudoxanthoma elasticum
adventitia and muscularis. Mycotic aneurysms are usually
Marfan syndrome
bacterial in nature. The most common organism is strepto-
Medical conditions associated with cerebral aneurysms
coccus, followed by Staphylococcus aureus and enterococ-
Fibromuscular dysplasia
cus. Fungal intracranial aneurysms caused by aspergillus
Systemic lupus erythematosus and other fungi rarely occur and are more commonly
Sickle cell disease caused by contiguous spread.
Intracranial arteriovenous malformations Mycotic aneurysms may be an incidental finding, but
Moyamoya disease they can also cause headache due to compression or rup-
Coarctation of the aorta ture, leading to intracranial hemorrhage. They commonly
Bicuspid aortic valve occur distally in the arterial tree, a central feature that dif-
ferentiates them from saccular aneurysms (Figure 53.3).
They sometimes can be detected on MRI, MRA, or CTA, but
they may be too small and too distal to be seen with any
imaging other than conventional angiography. Treatment
inconsistently predictive of rupture. Family history of includes antibiotic therapy and, in some cases, surgical
aneurysm may also indicate a higher risk of rupture. treatment.
A large international epidemiologic cohort study (the
International Study of Unruptured Intracranial Aneurysms) Fusiform Aneurysms
assessed the risk of aneurysm hemorrhage among patients Fusiform aneurysms and dolichoectasia (dolicho=tortuous;
with UIA. The 5-year cumulative rupture rates from that ectasia=dilatation) are relatively uncommon with an over-
study are shown in Table 53.1. The PHASES score is also all frequency of detection that is less than 1%. Risk factors
used to predict which aneurysms may rupture (Table 53.2). include smoking, hypertension, male sex, and older age.
Fusiform aneurysms and dolichoectasia are most common
Treatment Interventions in the posterior circulation. An imaging diagnosis is based
Management options for UIAs include conservative treat- on dilatation of an arterial segment, 1.5 times the normal
ment with follow-up or an interventional procedure with size and without a definable neck (Figure 53.4). These non-
surgical clipping and endovascular management, the most saccular intracranial aneurysms (NIAs) can sometimes be
common of which is placing tiny platinum coils directly suggested on cross- sectional imaging of the head with
into the aneurysm. Other endovascular options are evolv- unenhanced CT or on MRI of the brain; they then can be
ing, including stent-assisted coiling, web device, and flow- further characterized on MRA or CTA. NIAs are most com-
diverting stents. Optimal treatment is selected according to monly detected in patients older than 60 years with a his-
the predicted risk of rupture, treatment risks, patient age, tory of hypertension and tobacco use. Patients may present
and presence of comorbidities. No direct comparison stud- with SAH, ischemia, or mass effect with compression of
ies of unruptured aneurysms have been performed, but a the pons or as an incidental radiologic finding. The risk of
randomized clinical trial of ruptured aneurysms did suggest hemorrhage may be as high as 2% annually, but the risk of
A B
Figure 53.2 Unruptured Anterior Communicating Artery Aneurysm. Conventional angiography (A) and conventional
angiography with 3-dimensional reconstruction (B) show a 7×9-mm saccular aneurysm (arrow in both A and B) of the
anterior communicating artery segment.
cerebral infarction is as high as 6% annually. Treatment fusiform appearance. MRA, CTA, or cerebral angiography
options are limited. Flow-diverting stents or surgical treat- may be useful for distinguishing between dissecting aneu-
ment may be considered. rysms and more common acquired aneurysms. Suggestive
characteristics include evidence of a false lumen, an intimal
Dissecting Aneurysms flap, and retention of contrast agent in the lumen or a taper-
Dissecting aneurysms are false aneurysms resulting from an ing of the artery at the proximal end. Dissecting aneurysms
intimal tear and intramural hemorrhage. Their location is are most commonly caused by trauma. Clinical presenta-
most typically extracranial, and they can have a saccular or tions include transient ischemic attack or cerebral infarction
Table 53.1 • Five-Year Cumulative Rupture Rates According to Size and Location of
Unruptured Aneurysm
<7 mm
Location Group 1 Group 2 7–12 mm 13–24 mm ≥25 mm
Cavernous carotid artery (n = 210) 0 0 0 3% 6.4%

AC, MC, or IC (n = 1,037) 0 1.5% 2.6% 14.5% 40%
Post-P comm (n = 445) 2.5% 3.4% 14.5% 18.4% 50%

Abbreviations: AC, anterior communicating or anterior cerebral artery; IC, internal carotid artery (not
cavernous carotid artery); MC, middle cerebral artery; post-P comm, vertebrobasilar, posterior cerebral
arterial system or posterior communicating artery.
From Wiebers DO, Whisnant JP, Huston J 3rd, Meissner I, Brown RD Jr, Piepgras DG, et al; International
Study of Unruptured Intracranial Aneurysms Investigators. Unruptured intracranial aneurysms: natural
history, clinical outcome, and risks of surgical and endovascular treatment. Lancet. 2003 Jul
12;362(9378):103-10; used with permission.
• About 0.5%-2% of the US population have a UIA.

Table 53.2 • Predictors Composing the PHASES Aneurysm
• About 85% of typical saccular aneurysms occur
Rupture Risk Score
anteriorly in the Circle of Willis, with common sites
PHASES Aneurysm Risk Scorea Points including the internal carotid artery terminus,
posterior communicating artery origin, anterior
(P) Population
North American, European (other than Finnish) 0 communicating artery to anterior cerebral artery
Japanese 3 junction, and proximal middle cerebral artery.
Finnish 5 • Screening is typically recommended for the first-
(H) Hypertension degree relatives of affected family members when there
No 0 is a history of ≥2 family members with SAH or brain
Yes 1 aneurysm.
(A) Age • The risk of aneurysm rupture appears to depend on
<70 y 0 aneurysm size, location, age, population, history of
≥70 y 1 hypertension, and prior SAH. The PHASES score may
(S) Size of aneurysm aid in prediction of rupture.
<7.0 mm 0 • Treatment of the aneurysm depends on the natural
7.0-9.9 mm 3 history, risk of treatment, and patient preference.
10.0-19.9 mm 6
≥20.0 mm 10
(E) Earlier SAH from another aneurysm
No 0 Intracranial Vascular Malformations
Yes 1
Arteriovenous Malformations
(S) Site of aneurysm
ICA 0 Arteriovenous malformations (AVMs) consist of pial arter-
MCA 2 ies shunting directly to veins without an intervening nor-
ACA/Pcom/posterior 4 mal capillary bed. They are typically single and located in
a
To calculate the PHASES risk score for an individual, the number of the supratentorial region. Histologically, AVMs are clusters
points associated with each indicator can be added up to obtain the of normal or dilated arteries and abnormal veins with cal-
total risk score. For example, a 55-year-old North American man with
no hypertension, no previous SAH, and a medium-sized (8 mm)
cification; some show evidence of prior hemorrhage.
posterior circulation aneurysm will have a risk score of Patients with AVMs generally present between the ages
0+0+0+3+0+4=7 points. According to Figure 3 in the source of 20 and 40 years, and AVMs occur equally in men and
publication, this score corresponds to a 5-year risk of rupture of 2.4%.
women. Frequency of detection increases with age, with
Abbreviations: ACA, anterior cerebral arteries (including the anterior
cerebral artery, anterior communicating artery, and pericallosal about one- half presenting with hemorrhage and other
artery); ICA, internal carotid artery; MCA, middle cerebral artery; symptoms, including seizures, headache, focal neurologic
Pcom, posterior communicating artery; posterior, posterior circulation deficit, and pulsatile tinnitus.
(including the vertebral artery, basilar artery, cerebellar arteries, and
Unenhanced CT has a relatively low sensitivity, but cal-
posterior cerebral artery); SAH, subarachnoid hemorrhage.
From Greving JP, Wermer MJ, Brown RD Jr, Morita A, Juvela S, Yonekura cification and hypointensity may be noted. AVM is visual-
M, et al. Development of the PHASES score for prediction of risk of ized with contrast medium enhancement. MRI of the brain
rupture of intracranial aneurysms: a pooled analysis of six is more sensitive, with findings that include hemosiderin
prospective cohort studies. Lancet Neurol. 2014 Jan;13(1):59-66. Epub
deposition and signal voids on T1-and T2-weighted imag-
2013 Nov 27; used with permission.

ing (Figure 53.5). MRA or CTA can add more detail. Cerebral
arteriography provides the most detailed information, fully
characterizing the feeding arteries and draining veins.
and, rarely, aneurysm rupture. When the aneurysms extend The natural history of AVMs suggests a risk of hemor-
intracranially, patients can present with ischemia or, with rhage of 2% to 4% annually, with a risk of recurrent hem-
the intradural extension, SAH. Surgical or endovascular orrhage of 6% to 17% in the first year after the initial
repair may be needed for some of these patients. hemorrhage. Thereafter, the risk decreases. Clinically,
prior hemorrhage is a strong predictor of hemorrhage.
Neoplastic Aneurysms Other predictors include: impaired venous drainage, sin-
Neoplastic aneurysms are rare, but they can occur with gle draining vein, deep venous drainage, or presence of
some types of primary and metastatic brain tumors. They intranidal aneurysm.
typically occur distally in intracranial arteries. Tumor Unruptured AVM lesions may be treated with observa-
emboli that infiltrate and weaken the vessel wall may tion, surgery, radiosurgery, or endovascular therapy.
result in aneurysm formation. Radiosurgery is often used for small (<3 cm) deep lesions,
A B
Figure 53.3 Infectious (Mycotic) Aneurysm. A, Coronal magnetic resonance image, T1-weighted with gadolinium shows
area of enhancement in right frontal lobe. B, Conventional angiogram shows 3 small fusiform aneurysms (arrows) of the
opercular branch of the right middle cerebral artery.
(From Flemming KD. Principles of critical care neurology. In: Mowzoon N, Flemming KD, editors. Neurology board review: an illustrated
study guide. Rochester [MN]: Mayo Clinic Scientific Press and Florence [KY]: Informa Healthcare USA; c2007. p. 401-34; used with
permission of Mayo Foundation for Medical Education and Research.)
A B
Figure 53.4 Angiograms of a Fusiform Aneurysm of the Basilar Artery. A, Anteroposterior view. B, Lateral view.
(From Flemming KD, Wiebers DO, Brown RD Jr, Link MJ, Nakatomi H, Huston J 3rd, et al. Prospective risk of hemorrhage in patients with
vertebrobasilar nonsaccular intracranial aneurysm. J Neurosurg. 2004 Jul;101(1):82-7; used with permission.)
and microsurgical treatment is often used for ruptured AVMs, Developmental Venous Anomalies
lesions with a predicted high risk of rupture, and lesions of
A DVA is composed of thin-walled venous channels and
patients with a predicted low surgical morbidity risk.
normal intervening neural tissue. DVAs are often inciden-
tal findings. MRI with contrast medium and susceptibility-
Cavernous Malformations
weighted MRI are more sensitive than CT and generally
Cavernous malformations are acquired lesions—typically show a radial pattern, which is the classic caput medusae
well-circumscribed, small, popcornlike lesions—that can pattern (Figure 53.7). DVAs are commonly detected at
appear in either the brain or the spinal cord. The overall autopsy (in up to 3% of all autopsies).
frequency of detection is about 0.5%. Diagnosis is most Most often, DVAs are detected on CT or MRI of the
common in the fourth and fifth decades, but patients can brain with no associated symptoms. Rarely, they may be
present in infancy and during childhood. The malforma- associated with seizures or with sensory or motor deficits;
tions occur equally in men and women. spontaneous thrombosis of a venous malformation may
Cavernous malformations may be sporadic or inher- cause hemorrhage, infarct, seizure, or compression of a
ited, or they may develop after therapeutic radiation. The cranial nerve at the root entry zone. DVAs may be associ-
sporadic form is characterized most commonly by a single ated with cavernous malformations. When a patient does
lesion, often associated with a developmental venous present with clinical symptoms, it is important to look for
anomaly (DVA). In the familial form, multiple lesions are a concomitant cavernous malformation with hemosiderin-
common. Three inherited forms of cerebral cavernous mal- sensitive MRI sequences.
formation (CCM) have been elucidated: CCM1, CCM2, and In general, these lesions are thought to have a benign
CCM3 (Table 53.3). natural history with a hemorrhage risk of less than 0.5%
Grossly, these lesions are well circumscribed, lobu- per year. Removal of a DVA is not recommended because
lated, and mulberrylike. Electron microscopy shows dys- of the extremely low risk of hemorrhage that is present and
function of the endothelial tight junctions. because the DVA functions as a draining vein to normal
A cavernous malformation is most readily detected on brain tissue.
MRI with a combination of high and low T1-and T2-
weighted signals that show the surrounding hemosiderin Dural Arteriovenous Fistulas
(Figure 53.6). Sporadic cavernous malformations are often
A dural arteriovenous fistula is a vascular malformation of
seen in combination with developmental venous anoma-
the wall of one of the major venous sinuses. The fistula
lies. Cerebral angiography is usually negative in the clini-
typically is acquired. Patients present between the ages of
cal setting of a cavernous malformation and is typically
40 and 60 years. Risk factors for fistula development
not recommended.
include prior history of sinus thrombosis and head trauma.
Patients with cavernous malformation can present with
Patients may present with pulsatile tinnitus, hemorrhage,
hemorrhage, seizure without hemorrhage, or focal neuro-
seizure, or focal neurologic deficit. Patients with cavernous
logic deficit without hemorrhage. In many cases, the cav-
sinus lesions may have double vision and exophthalmos.
ernous malformation is an incidental finding.
MRI with MRA is more sensitive than CT in showing the
The prospective risk of hemorrhage depends on the
diagnostic dilated veins and feeding arteries. Cerebral arte-
nature of the initial diagnosis and the location of the
riography with selective external carotid artery injection is
lesion. If patients present with seizures or a lesion is inci-
the gold standard for their detection and characterization.
dentally detected, the overall risk of a clinically apparent
The overall risk of hemorrhage is about 2% annually

hemorrhage is less than 1% annually. The 5-year risk of
and varies with the hemorrhage site and hemodynamics.
recurrent hemorrhage is as high as 30% among patients
Risk factors for future hemorrhage include cortical venous
who have had a symptomatic hemorrhage and the lesion is
drainage and hemorrhage at the patient’s presentation.
in the brainstem.
Treatment options include surgical excision, radiosur-
Conservative management with observation is often
gery, or embolization.
recommended for cavernous malformation of asymp-
tomatic patients. Surgical excision may be performed if
Capillary Telangiectasias
a patient has had 1 or multiple episodes of clinically or
radiographically apparent hemorrhage or the patient has Capillary telangiectasias are somewhat enlarged ectatic
poorly controlled epilepsy and the lesion is accessible. capillaries. They are typically noted in the posterior fossa
Ongoing research suggests a role for medications (pons) or spinal cord on MRI with a contrast agent. They are
that may modify the disease course. Clinical trials are unlikely to cause symptoms and, in general, do not require
underway. any treatment. Occasionally, capillary telangiectasias can
A B
C D
Figure 53.5 Continued
Figure 53.5 Right Parietooccipital Arteriovenous Malformation (AVM). A and B, T2-weighted magnetic resonance image
(MRI) shows flow voids consistent with AVM (arrowheads). C, T1- weighted MRI with contrast agent shows partial
enhancement of the AVM (arrow). D and E, Arteriograms with vertebral injection. Anteroposterior view (D) and lateral view
(E) show posterior cerebral artery feeders (small arrows) to the AVM (arrowheads), with a large draining vein into the
superior sagittal sinus (curved arrows).
(From Brown RD Jr, Flemming KD, Meyer FB, Cloft HJ, Pollock BE, Link ML. Natural history, evaluation, and management of intracranial
vascular malformations. Mayo Clin Proc. 2005 Feb;80[2]‌:269-81; used with permission of Mayo Foundation for Medical Education and
Research.)
be large and mistaken for a mass lesion (eg, tumor). Vein of Galen Malformations
However, MRI with contrast medium and hemosiderin
Vein of Galen malformation is a type of arteriovascular
sequences (eg, susceptibility-weighted imaging, gradient-
malformation that affects the median vein, which develops
recall echo) can help distinguish a tumor and a vascular
into the true vein of Galen. This malformation is present
malformation.
during gestation and often leads to heart failure in
Table 53.3 • Genetics of CCM

Type of CCM
Feature CCM1 CCM2 CCM3
Locus 7q11-q22 7p15-13 3q25.2-q27

Gene KRIT1 MGC4607 (malcavernin) PDCD10
Clinical Common in Hispanic population ... Often, presentation in childhood
May be associated with scoliosis
and benign brain tumors
Abbreviation: CCM, cerebral cavernous malformation.
Figure 53.7 Developmental Venous Anomaly. Coronal T1-

weighted contrast-enhanced magnetic resonance imaging
shows a left cerebellar developmental venous anomaly
Figure 53.6 Cavernous Malformation (CM). Axial T2-
(arrow).
weighted magnetic resonance image shows characteristic
appearance of CM in deep gray matter. The area with the
characteristic, reticulated “mulberry” or popcornlike concomitant cerebral vascular malformations, cerebral isch-
appearance is surrounded by a hypointense rim consistent emia, or abscesses due to associated pulmonary shunts. To
with hemosiderin deposition. prevent further cerebral ischemia, pulmonary shunts are
(From Flemming KD. Cerebrovascular disease. In: Mowzoon N, coiled and obliterated. (See also Chapter 119, “Neurocutaneous
Flemming KD, editors. Neurology board review: an illustrated Disorders.”)
Florence [KY]: Informa Healthcare USA; c2007. p. 435-84; used Sturge-Weber Syndrome
Sturge-Weber syndrome is a vascular disorder with a lepto-
Research.)
meningeal capillary- venous malformation affecting the
brain. Ipsilateral to the vascular malformation, a port-wine

newborns or the development of hydrocephalus (because stain (ie, a facial capillary malformation) is often present.
of interference with venous return). In some cases, the Patients may present with focal neurologic deficits, sei-
diagnosis is delayed from infancy when patients present zures, or cognitive issues. Patients are also at risk for glau-
with headache or other neurologic symptoms. coma. The cause of Sturge-Weber syndrome is a somatic
MRI of the brain can suggest the diagnosis, and angiog- mosaic mutation in the GNAQ gene.
raphy confirms the diagnosis (Figure 53.8).
• Patients with AVMs generally present between the ages
Osler-Weber-Rendu Disease (Hereditary of 20 and 40 years.
Hemorrhagic Telangiectasia) • The risk of hemorrhage from an AVM is 2%-4%
annually, with a risk of recurrent hemorrhage of
Olser-Weber-Rendu disease is an autosomal dominant vascu-
6%-17% in the first year after an initial hemorrhage.
lar disorder. Typically, patients present in childhood to early
Thereafter, the risk decreases.
adulthood with epistaxis or episodes of gastrointestinal tract
• Cavernous malformations may be sporadic or
bleeding. Patients often have tiny telangiectasias on their lips
inherited. The KRIT1 mutation commonly occurs in
or fingertips. Neurologic manifestations may include
A B
Figure 53.8 Vein of Galen Malformation. The patient was a newborn who became lethargic and apneic after birth. A,
Computed tomography shows an enlarged vein of Galen and hydrocephalus. B, Conventional angiography confirms the
massively enlarged vein of Galen.
the Hispanic population and is the most common • Vein of Galen malformation is a type of arteriovascular
familiar form of cavernous malformation. malformation that affects the median vein, which
• Dural arteriovenous fistulas are typically acquired. develops into the true vein of Galen. This malformation
Patients present between the ages of 40 and 60 years is present during gestation and often leads to heart
with pulsatile tinnitus, hemorrhage, seizure, visual failure in newborns or the development of
symptoms, or focal neurologic deficit. hydrocephalus (due to interference with venous return).
Neurorehabilitationa
54 BILLIE A. SCHULTZ, MD
Introduction diagnoses, are expected as patient needs continue to grow

over their lifespan.
P
hysical medicine and rehabilitation—physiatry—is
the medical specialty focusing on the restoration of
functional status of patients with musculoskeletal,
nervous system, or congenital disorders. The World
Rehabilitation Setting and
Health Organization defined disability and created the Rehabilitation Team
International Classification of Functioning, Disability, Interdisciplinary Team
and Health. With this classification, a physiatrist addresses
the 3 domains of disability: impairment, activity limita- The rehabilitation team is multidisciplinary. Led by a phys-
tion, and restricted participation (Table 54.1). iatrist and the patient, team members may include the
This approach accounts for the patient’s health status patient’s primary care physician, specialty care physicians
in addition to personal and environmental factors that may (eg, neurologist, neurosurgeon, orthopedic surgeon), nurses,
be barriers to participation. For example, in a nonaccessi- therapists (occupational, physical, recreational, music, or
ble community, a person with spinal cord injury (SCI) may speech and language therapists), psychologists, and social
be restricted from participation. In an accessible commu- workers. Often, a prosthetist or an orthotist has a central role.
nity with adequate parking, curb cutouts, and ramps, this The rehabilitation plan depends on the patient’s prognosis:
person is less restricted. Physiatrists work together with Is the underlying disease expected to resolve, stabilize, or
the patient, the patient’s community, and an interdisci-
plinary health care team to address impairment, activity
limitation, and restricted participation for patients, regard-
Table 54.1 • ICF Domains of Functioning and Disability
less of their diagnosis.
The life expectancy is increasing for many persons with Functioning Disability
neurologic injury, despite the potentially devastating con-
Body functions and structures Impairments
sequences of their injury. Quality of life, including inde-
Activities Activity limitations
pendence, safety, and function, need to be addressed.
Coordinated rehabilitation services with evidence-based Participation Restriction in participation
interventions may affect all 3 domains of disability. Further Abbreviation: ICF, International Classification of Functioning, Disability,
advances in neurorehabilitation, with implications for all and Health.
a
Portions previously published in Brown AW, Schultz BA. Recovery and rehabilitation after stroke. Semin Neurol. 2010 Nov;30(5):511-7.
Epub 2011 Jan 4; used with permission.
Abbreviations: ADL, activities of daily living; AFO, ankle-foot orthosis; ALS, amyotrophic lateral sclerosis; LMN, lower motor neuron;
rTMS, repetitive transcranial magnetic stimulation; SCI, spinal cord injury
440
Chapter 54. Neurorehabilitation 441
progress? Equipment needs, physical or cognitive external neuromuscular facilitation and technical approaches
supports, and dismissal location differ according to the neu- developed by Brunnstrom, Bobath, and Rood (Table 54.2).
rologist’s prognostic opinion. These strategies continue to be used frequently. Emerging
therapeutic techniques are being explored, sometimes to
Levels of Rehabilitation augment the older techniques. Each therapy is individual-
ized to the patient and their needs, often combining mul-
A patient’s needs determine the level of ongoing care,
tiple therapy philosophies and modalities.
which may include rehabilitation services during acute
Historically, the focus of therapy was called learned
care hospitalization, specialized acute inpatient rehabilita-
disuse, in which the patient avoids use of the affected limb
tion, transitional care at a subacute care rehabilitation
and is trained to use the unaffected limb for all activities.
facility, or outpatient rehabilitation services, including day
In contrast, current thought is that avoiding use of the
programs with a focus on community reentry.
affected limb may hinder participation in restorative thera-
pies. Constraint- induced movement therapy involves
restraint of the unaffected limb, effectively forcing the use
Rehabilitation for Stroke of the affected limb in intensive motor shaping and repeti-
Specific Techniques in Stroke Rehabilitation tive task practice directed by a clinician. The Extremity
Constraint Induced Therapy Evaluation trial showed sta-
As survival improves following stroke, more older persons tistically significant and clinically important improvement
are living with residual symptoms, making stroke the lead- in arm motor function that lasted 1 year compared with
ing cause of activity limitation related to neurologic condi- traditional therapy. The study required use of a restraint
tions in adults. Brain plasticity after focal cortical infarctions for 90% of the patient’s waking hours and clinician-
has been well documented and can be molded by specific directed care for up to 6 hours daily for 14 consecutive
motor tasks. Willful, repetitive, task-specific activity results days. Although the results looked promising, the intensity
in cortical structure changes, including increased dendritic of this therapy presents personnel and financial challenges
arborization, synaptogenesis, and synaptic density. These in a clinical situation.
changes translate into functional improvements in the Robotic technology is another emerging area of therapy
patient’s level of impairment. for neurologic injury. Devices have been developed for the
Initiation of rehabilitation within 72 hours after stroke upper and lower limbs. Benefits of these devices are the
is an established guideline to take advantage of brain plas- possibility of multiple, consistent repetitions of specific
ticity. Many therapeutic techniques are used to treat neu- motion patterns. Most research involving the robot-driven
rologic impairment after stroke, including proprioceptive gait orthoses has been done for SCI rather than stroke. A
less expensive option for locomotion training is a harness-
based, partial body weight–supported gait orthosis, which
Table 54.2 • Principles of Established and Emerging requires more physical assistance by the therapist.
Therapeutic Techniques for Patients Movement can be facilitated through neuromuscular
After Stroke electrical stimulation, both percutaneous and implantable,
which activates the lower motor neuron (LMN). It allows
Therapy Method
for contraction of the paretic muscle and thus facilitates
Proprioceptive Use resistance provided by stronger movement during functional tasks and ambulation.
neuromuscular muscles to facilitate the weaker One therapy applies a user-computer interface in vir-
facilitation components of the same motion pattern
tual reality. It involves real-time simulation of an environ-
Brunnstrom Take advantage of the stronger muscles ment or activity through the interface and allows for
and the primitive postural reactions to
training in complex environments, adaptive changes in
facilitate synergistic motor patterns in
early recovery interactive parameters during sensorimotor performance,
Incorporate isolated movements at later and multimodality sensorimotor feedback. This technol-
stages of recovery ogy may have more important implications in telemedi-
Bobath Use reflexive movement patterns to cine because therapy can be guided from a distance.
inhibit increased tone Repetitive transcranial magnetic stimulation (rTMS) is
Rood Use tactile stimulation to facilitate muscle being investigated. Optimal timing of treatment, suppres-
movements sion compared with activation of the brain cortex, and the
dose of rTMS are unknown. Further investigation will
Constraint-induced Require forced use of the affected limb by
movement restraining the unaffected limb during explore whether rTMS can be an appropriate adjuvant
treatment sessions treatment with conventional therapies.
Table 54.3 • Commonly Used Medications to Treat Spasticity

Medication Mechanism of Action Adverse Effects Dosage
Baclofen Agonist of presynaptic GABAB Sedation, weakness, GI tract Initially, 5 mg 3 times daily
receptors, inhibiting calcium influx symptoms, tremor, insomnia, Increase by 15 mg daily every 3 d
into presynaptic terminals and confusion Maximum, 80 mg daily divided 3 or
suppressing the release of 4 times daily
excitation neurotransmitters
Dantrolene Reduces calcium release by Hepatotoxicity (1% of patients), Initially, 25 mg daily
sarcoplasmic reticulum, inhibiting drowsiness or sedation, weakness, Increase by 25-50 mg every 4-7 d
skeletal muscle contraction fatigue, diarrhea, nausea, vomiting Maximum, 400 mg divided 4 times
daily
Diazepam Enhances action of GABAA receptors, Sedation, memory impairment Initially, 2 mg twice daily
inhibiting muscle contraction Increase as needed
Maximum, 60 mg daily divided
2-4 times daily
Tizanidine α-Adrenergic agonist, increasing Drowsiness, hypotension, dry mouth, Initially, 2-4 mg daily
presynaptic inhibition of motor bradycardia, dizziness Increase by 2-4 mg over 2-4 wk
neurons Maximum, 36 mg daily divided 3 or
4 times daily
Abbreviations: GABA, γ-aminobutyric acid; GI, gastrointestinal.
the foot and ankle joint. Depending on the ankle joint posi-
Specific Rehabilitation Issues for Persons
tioning, the knee also may be stabilized to improve the
With Stroke
gait. Plantar flexion at the ankle creates a knee extension
Swallowing is a complex biologic function involving many moment during gait, effectively stabilizing the knee. A bal-
muscles that are controlled voluntarily and involuntarily. Not ance between dorsiflexion for foot clearance and plantar
surprisingly, impaired swallowing, or dysphagia, occurs in flexion for knee stabilization needs to be met. AFOs can be
one-third to three-fourths of patients after stroke. Evaluation designed with little or more restriction at the ankle joint.
of swallowing can include bedside testing, videofluorogra- The more restrictive braces do not allow ankle movement
phy, and fiberoptic endoscopy. Speech pathologists do most in any direction, including plantar, dorsiflexion, eversion,
of these evaluations, and assistance can be provided by occu- and inversion. A more restrictive brace can minimize the
pational therapists specially trained in dysphagia evaluation potential for injury, but it does alter gait mechanics, which
and treatment. Ensuring appropriate hydration and nutrition should be taken into account.
is essential when dysphagia is present. Other bracing or orthotic options for the lower extremi-
If swallowing is not expected to improve within the first ties include and support more proximal joints. For patients
2 to 3 weeks after a stroke, percutaneous endoscopic gas- with proximal upper- extremity impairment, a balanced
trostomy feeding should be considered. A 2015 Cochrane forearm orthosis can be considered. This orthosis can min-
Review concluded that percutaneous endoscopic gastros- imize the pull of gravitational forces and allow the patient
tomy is effective and safe, with decreased probability of to have easier use of the affected limb to complete their
intervention failure and greater feed delivery than nasogas- ADLs. The patient’s therapist and orthotist can work
tric tube feeding. Other treatment includes compensatory together to determine the least restrictive device that ade-
techniques to ensure safe swallowing and therapy to quately addresses the patient’s needs.
improve swallowing. If vocal cord paralysis is suspected, Spasticity after stroke is a velocity-dependent increase
an otolaryngologic evaluation may be indicated for consid- in tonic stretch reflexes and potentially can contribute to
eration of vocal cord medialization. neurologic impairment and cause pain. All patients should
A hallmark of stroke is weakness, which is the residual be educated on the importance of stretching to manage
symptom most noted by the patient. Weakness can result in spasticity. Orthotic devices also are used to treat spasticity
poor sitting posture, impairment in activities of daily living (eg, AFOs for prevention of plantar flexion) and to promote
(ADL), and impaired locomotion. More than 85% of patients elbow, wrist, and finger extension. Static and dynamic
can ambulate after a stroke; a smaller percentage may be splints provide a constant low level of resistance. In addi-
functional community ambulators. Adaptive equipment, tion to stretching and splinting, other commonly used
such as a cane, walker, or brace, can improve their mobility. methods for spasticity management include 1) oral medi-
An orthotic device commonly used after stroke is an cation (Table 54.3), 2) chemodenervation by either a lytic
ankle-foot orthosis (AFO). This orthotic device includes agent (alcohol or phenol) or a neuromuscular blocking
Chapter 54. Neurorehabilitation 443
agent (botulinum toxin), and 3) delivery of medication repetitions and is less labor intensive, but some health care
directly to the intrathecal space. Orthopedic surgical con- providers question its effectiveness. Robotically powered
sultation should be considered for spasticity that cannot exoskeletons as gait orthoses are under investigation to
be managed adequately with conservative treatments. determine whether they allow safe ambulation in a com-
munity setting for a person with paraplegia. Other equally
• Initiation of rehabilitation within 72 hours after stroke important considerations besides locomotion are rehabili-
is an established guideline to take advantage of brain tation that includes wheelchair mobility, transfers, bowel
plasticity. and bladder management, pressure relief, and increasing
• Constraint-induced movement therapy involves independence in ADL. Patient and family education that
restraint of the unaffected limb, which effectively stresses the importance of all physical skills training is
forces use of the affected limb in intensive motor essential.
shaping and repetitive task practice directed by a Autonomic dysreflexia affects patients who have an
clinician. injury at T6 or above. This results in an uninhibited sym-
• In addition to stretching and splinting, other pathetic response to noxious stimuli. Symptoms typically
commonly used methods for spasticity management include headache, blood pressure higher than baseline,
are oral medication, chemodenervation by a lytic agent diaphoresis, facial flushing, pupillary dilatation, and bra-
(alcohol or phenol) or a neuromuscular blocking agent dycardia. If untreated, autonomic dysreflexia can lead to
(botulinum toxin), and medication delivery directly to prolonged hypertension, cerebral hemorrhage, or death.
the intrathecal space. Treatment consists of loosening the patient’s clothes, sit-
ting the patient up, and trying to identify the source of
noxious stimuli (often bladder related). If needed, fast-
Rehabilitation for SCI acting antihypertensive agents can be administered.
Common choices include nitroglycerin paste applied
Spinal Cord Injury above the level of the SCI or oral nifedipine.
SCI can be devastating to the patient and their family. Depending on the spinal level of injury, various changes
Historically, a patient with the diagnosis of SCI had a to the urinary system can be observed. If the injury occurs
shorter life span. However, since the 1960s and with above the sacral segments, the result is a so-called upper
improved medical knowledge, medications, and tools motor neuron bladder, in which urination cannot be initi-
available, life expectancy has increased for SCI and is ated by voluntary relaxation of the external sphincter.
approaching normal. SCI can be traumatic or nontraumatic Coordination is lost between the detrusor and external
and can be related to cancer, infection, inflammatory pro- bladder sphincter, often resulting in detrusor- sphincter
cess, or ischemia. Prognoses are better defined for patients dyssynergy or a low-volume–high-pressure bladder with
with traumatic SCI. Depending on the level and complete- or without incontinence. Conversely, an injury at the sacral
ness of injury as defined by the International Standards for level results in an LMN or areflexic bladder. Typically, this
Neurological Classification of Spinal Cord Injury, the infor- patient has a high-volume–low-pressure bladder and over-
mation that can be shared with the patient and family flow incontinence.
includes expected outcomes in locomotion, respiratory Goals of bladder management are to achieve a socially
support, ADL, bowel and bladder management, and pres- acceptable emptying of the bladder and to reduce the risk
sure relief. Close follow-up with a physiatrist who has sub- of infection, calculi, and renal failure. The most common
specialty training and certification in SCI is recommended method of bladder emptying is intermittent catheteriza-
because patients with SCI are at risk for complications spe- tion, either by oneself or by a surrogate. The patient has a
cific to their injury. fluid schedule and a catheterization schedule with a goal
of dryness between catheterizations and catheterized vol-
umes of less than 500 mL (in the adult population).
Specific Rehabilitation Issues for Persons
Tetraplegic patients or patients who cannot perform self-
With SCI
catheterization and who do not have a surrogate available
Mobility limitations due to SCI can affect a patient’s life have the option of indwelling catheterization (either ure-
satisfaction. The spinal cord has the potential to generate thral or suprapubic). For patients with detrusor-sphincter
motor control, allowing full weight- bearing locomotion dyssynergy, the goals of therapy include minimization of
without supraspinal influence. Patients and clinicians glomerular pressure and prevention of reflux to the kid-
should address mobility training. neys. Both can result in kidney damage. This risk is mini-
Overground mobility training, body weight support mized by increasing the bladder volume with the use of
ambulation training on a treadmill, and robotic- assisted anticholinergic agents, botulinum toxin injections, or
training are forms of locomotor training currently used. No bladder augmentation. Patients should be evaluated regu-
training method is superior to another. The argument for larly by a urologist, preferably one with a special interest
robotic-assisted training is that it provides identical pattern in neurologic urologic disease processes.
Similar to the effect of neurogenic bladder, SCI alters of an acute event, recovery, plateau, and community
bowel function. If the injury occurs above the sacral levels, re
entry. The Medical Advisory Board of the National
defecation cannot be initiated by voluntary relaxation of Multiple Sclerosis Society recommends referral for reha-
the external anal sphincter, although reflex- mediated bilitation services. Early referral is preferred, but referral is
colonic peristalsis can occur. The so-called LMN bowel is often delayed until fixed functional deficits are present. It
due to injuries that occur at the sacral level. These injuries is unclear whether functional recovery is related to neural
result in an areflexic bowel that has no reflex-mediated plasticity or to appropriate compensatory techniques.
colonic peristalsis and has only slow stool propulsion Symptom management is a focus of the rehabilitation
coordinated by the intrinsically innervated myenteric endeavors and includes management of neurogenic blad-
plexus. Because the sphincter is typically atonic, leakage der and bowel, spasticity, weakness, fatigue, visual impair-
of stool can result. ment, depression, and cognitive dysfunction. An exercise
Bowel program goals have similar goals as those of program can improve the patient’s symptoms of fatigue,
bladder programs: to achieve a socially acceptable empty- but the program may need to be initiated in a supervised
ing of the bowel while maintaining bowel evacuation. setting to encourage and guide the patient.
Programs should be regularly scheduled to ensure com-
plete emptying on a consistent basis. Typically, dietary Amyotrophic Lateral Sclerosis
fiber and medications are adjusted to modulate stool con-
A neurodegenerative disease such as amyotrophic lat-
sistency. For patients with an intact colonic reflex (ie,
eral sclerosis (ALS) leads to progressive function limita-
upper motor neuron bowel), mini-enemas and supposito-
tions, including dysphagia, communication limitations,
ries can be used. Digital stimulation can be used for
weakness, muscular atrophy, spasticity, fatigue, mobil-
patients with an intact sacral reflex. Digital evacuation (ie,
ity limitations, and respiratory compromise. Much of
manual evacuation of the stool) is more typically used for
the rehabilitation focus is on equipment procurement to
persons with an LMN bowel. Colostomy is used if a bowel
prepare for the future of expected changes, which will
program is not successful and the patient has bowel acci-
limit activity and restrict participation. For both a high
dents or soiling of wounds.
cervical SCI and ALS, pulmonary function is of con-
As in therapy after stroke, spasticity management is an
cern. Options for severely affected patients include ven-
important part of SCI rehabilitation. Most concepts are sim-
tilatory dependency. Exercise and strengthening for
ilar. The spasticity is more likely to be generalized for SCI
patients with ALS, an ongoing area of controversy, con-
than for a focal cortical infarction, so systemic medications
tinue to be explored. Animal studies show that moder-
such as baclofen, tizanidine, diazepam, and dantrolene are
ate exercise may be beneficial, but strenuous exercise
more likely to be used. In addition, intrathecal baclofen
may actually hasten the disease process. Owing to the
delivery has been effective for this patient population.
limitations of the published studies, including small
sample size and a limited number of studies on this sub-
• For patients with SCI, life expectancy has increased
ject, it is unclear whether these results apply to humans.
compared with the past and is now approaching
Because of these limitations, a 2013 Cochrane Review
normal.
could not state the degree to which strengthening is
• Autonomic dysreflexia affects patients who have an
harmful or beneficial.
SCI at T6 or above. This syndrome results in an
uninhibited sympathetic response to noxious stimuli.
Parkinsonism
Parkinsonism often affects movements, specifically caus-

Rehabilitation for Other Neurologic ing postural instability and bradykinesia. Cognitive deficit
and mood disturbances can be noted. Rehabilitation is
Diseases based more on practical experience than on clinical data. A
Multiple Sclerosis rehabilitation approach should be multifaceted and
include education, assessment of gait and balance, use of
Multiple sclerosis is usually a progressive disorder. Unlike assistive devices as needed, and consideration of cognitive
the examples above, it does not follow the disease course rehabilitation.
Questions and Answers
Questions
Multiple Choice (choose the best answer)
III.1. The most common cause of ischemic stroke is which of the
following?
a. Coagulation disorder
b. Large-vessel extracranial atherosclerosis
c. Vasculitis
d. Cardioembolic cause
e. Embolic stroke of undetermined source
III.2. For which of the following cases is carotid endarterectomy defi-
nitely indicated within 2 weeks?
a. Amaurosis fugax in the right eye with 80% internal carotid artery
stenosis by magnetic resonance angiography (MRA) of the neck
b. Transient right hemiplegia and aphasia with 50% internal carotid
artery stenosis by ultrasonography
c. Left hemispheric stroke with National Institutes of Health Stroke
Scale score of 30 and left internal carotid artery stenosis measur-
ing 90% by computed tomographic angiography (CTA) III.5. A patient with hypertension and diabetes mellitus presents with
d. Incidental 50% left internal carotid artery stenosis in an 85-year- right face, arm, and leg numbness. Examination shows decreased
old patient pin prick response on the right face, arm, and leg. Strength is
e. Transient weakness of the left face and arm and 100% occlusion normal. Where is the stroke localized?
of the right internal carotid artery of a 75- year-
old female a. Left anterior thalamus
patient b. Left lateral thalamus
III.3. What equally effective alternative to warfarin treatment do patients c. Left medulla
with nonvalvular atrial fibrillation have for stroke prevention? d. Left internal capsule
a. Aspirin 325 mg daily e. Left insular cortex
b. Aspirin 81 mg and clopidogrel 75 mg daily III.6. A 45-year-old man presents with right hemiparesis without sen-
c. Aspirin 81 mg daily and rivaroxaban 2.5 mg twice daily sory or language impairment. He acknowledges a long-standing
d. Apixaban 5 mg twice daily history of migraine headaches. His mother and maternal grand-
e. Clopidogrel 75 mg daily father have a history of stroke in their early 50s. Magnetic reso-
III.4. A patient presents with left homonymous hemianopia, left nance imaging shows an acute infarct in the left posterior limb
hemiplegia (face, arm, and leg), and left hemisensory loss (face, of the internal capsule and diffuse, confluent T2 hyperintensity
arm, and leg). A magnetic resonance image is shown herein. A within bilateral subcortical white matter and the anterior tem-
thrombus in which artery might produce this clinical picture? poral lobes. Which of the following is most likely the cause of
a. Right recurrent artery of Huebner this patient’s syndrome?
b. Right anterior division of middle cerebral artery a. Mutation in FBN1 gene
c. Right anterior choroidal artery b. Mutation in Notch3 gene
d. Right posterior cerebral artery c. Mutation in GLA gene
e. Right tuberothalamic artery d. Mutations in α-galactosidase A gene
e. Prothrombin 20210 mutation
445
III.7. A 41-year-old woman with a past medical history of hyperten- terminus occlusion and no acute head CT changes. By now, it is
sion, type 2 diabetes mellitus, migraine headaches, prior stroke 9 am. The patient’s blood pressure is 160/85 mm Hg; glucose,
1 year ago with residual mild right hemiparesis, and 2 miscar- 110 mg/dL; and international normalized ratio, normal. What
riages is referred for further evaluation of recurrent episodes of is the next step in treatment or evaluation?
left arm paresthesias. General examination shows a diffuse a. Admit the patient and start aspirin therapy at 325 mg daily
lacelike rash of the trunk and all extremities. Neurologic exam- b. Administer intravenous (IV) recombinant tissue plasminogen
ination shows mild right hemiparesis in an upper motor neu- activator (r-tPA) at 0.45 mg/kg
ron pattern but is otherwise unremarkable. Of the following c. Obtain CT perfusion or diffusion magnetic resonance imag-
syndromes and diseases, which is the most likely diagnosis? ing (MRI)
a. Eales syndrome d. Administer IV tenecteplase 0.25 mg/kg
b. Cogan syndrome e. Pharmacologically increase her blood pressure to 180/100 mm
c. Kohlmeier-Degos disease Hg to increase collateral perfusion
d. Sneddon syndrome III.13. Which of the following is not a component of the CHA2DS2-
e. Susac syndrome VASc Score?
III.8. A 30-year-old woman presents 2 weeks’ postpartum for head- a. Age
ache and double vision. The headache was initially holoce- b. Hypertension
phalic, dull, and only mildly bothersome. However, sudden c. Diabetes mellitus
worsening of the headache occurred and was followed by hori- d. Smoking
zontal diplopia and graying of her vision whenever she coughed e. Sex
or sneezed. On examination, she has papilledema and a cranial III.14. Which of the following modifiable risk factors has the greatest
nerve VI palsy. What is the most appropriate test to confirm the effect on stroke reduction?
most likely diagnosis for this patient? a. Hyperlipidemia
a. Magnetic resonance imaging b. Diabetes mellitus
b. Magnetic resonance angiography c. Hypertension
c. Magnetic resonance venography (MRV) d. Surgery for asymptomatic carotid stenosis
d. Lumbar puncture e. Weight reduction
e. Cerebrospinal fluid analysis III.15. A patient starts treatment with a direct oral anticoagulant (DOAC)
III.9. Which of the following is an absolute contraindication to intra- after a transient ischemic attack and concomitant atrial fibrilla-
venous (IV) administration thrombolytics? tion. Which of the following should you monitor at least annually?
a. Small parafalcine meningioma a. International normalized ratio
b. Hypertension with a systolic blood pressure of 200 mm Hg b. Partial thromboplastin time
before antihypertensive treatment c. Antifactor Xa
c. Suspicion for endocarditis or aortic dissection d. Creatinine
d. Cervical artery dissection e. Liver function
e. Warfarin therapy with an international normalized ratio of 1.6 III.16. The long-term blood pressure goal for patients after cerebral
III.10. What is the minimum National Institutes of Health Stroke Scale ischemia is which of the following?
(NIHSS) score before which intravenous (IV) thrombolytics a. 160/90 mm Hg
should be considered? b. 150/90 mm Hg
a. NIHSS score greater than 2 c. 140/90 mm Hg
b. NIHSS score greater than 5 d. 130/80 mm Hg
c. NIHSS score greater than 10 e. 120/80 mm Hg
d. NIHSS score greater than 15 III.17. A 78-year-old man presents with a basal ganglia hemorrhage.
e. No minimum NIHSS score The most likely cause in a patient this age with a hemorrhage
III.11. A 75-year-old patient who is independent in activities of daily in this location is which of the following
living and has a history of atrial fibrillation presents with acute a. Hypertension
right hemiplegia and aphasia and a National Institutes of b. Cerebral amyloid angiopathy
Health Stroke Scale score of 14. Intravenous (IV) thrombolytics c. Cavernous malformation
are contraindicated because the patient takes warfarin and has d. Arteriovenous malformation
an international normalized ratio (INR) of 1.8. Computed e. Reversible cerebrovasoconstrictive syndrome
tomography (CT) of the brain shows a dense left middle cere- III.18. Corticosteroids should be given in which of the following clini-
bral artery with no areas of hypodensity. CT angiography of the cal settings for a patient with cerebral hemorrhage?
head and neck confirms a left M1 middle cerebral artery occlu- a. Reversible cerebrovasoconstrictive syndrome
sion. Tests are completed at 2 hours from symptom onset. The b. Hypertensive hemorrhage with ventricular extension
next best step in management is which of the following? c. A large lobar hemorrhage with associated hydrocephalus
a. Admit patient to the hospital and start of IV administration of d. Warfarin-related intracerebral hemorrhage
heparin to bridge until INR is in a therapeutic range e. Generally not given for intracranial hemorrhage
b. Obtain a CT perfusion scan III.19. An 85-year-old man presents with acute hemorrhage in the cer-
c. Obtain magnetic resonance imaging of the brain ebellum with extension into the fourth ventricle and resultant
d. Take the patient to endovascular therapy for embolectomy and hydrocephalus. Glasgow Coma Scale score is 4 on presentation.
clot retrieval Which easy-to-use score system may help you predict a 30-day
e. Administer tenecteplase mortality rate?
III.12. A 68-year-old woman awakens in the morning with left hemi- a. Hunt-Hess Score
plegia and neglect and a National Institutes of Health Stroke b. Intraparenchymal cerebral hemorrhage (ICH) score
Scale score of 15. She was most recently normal the evening c. World Federation of Neurosurgeons Grading System (WFNS)
before at 10 pm. Computed tomography (CT) of the head and CT d. National Institutes of Health Stroke Scale
angiography of the head and neck show a right carotid e. Glasgow outcome score
Questions and Answers 447
III.20. Approximately what percentage of the US population has an III.24. Which of the following medications is not approved by the US
unruptured intracranial aneurysm? Food and Drug Administration for treatment of centrally medi-
a. 0.01% ated spasticity?
b. 2% a. Dantrolene
c. 10% b. Gabapentin
d. 20% c. Diazepam
e. 33% d. Baclofen
III.21. Which of the following factors increases the risk of rupture in e. Tizanidine
an incidentally found cerebral aneurysm? III.25. Which of the following conditions is a symptom of autonomic
a. Diabetes mellitus dysreflexia after spinal cord injury?
b. Polycystic kidney disease a. Bradycardia
c. Increasing size of aneurysm b. Hypotension
d. Location at the middle cerebral artery c. Hypothermia
e. Fibromuscular dysplasia d. Sweating below the level of the spinal cord injury
III.22. Which of the following types of vascular malformation most e. Diarrhea
commonly has a genetic and a sporadic form? III.26. Which of the following statements best describes constraint-
a. Arteriovenous malformation induced movement therapy used for patients with ischemic
b. Dural arteriovenous fistula stroke?
c. Cavernous malformation a. Tactile stimulation is used to facilitate muscle movements
d. Developmental venous anomaly b. The unaffected limb is restrained, forcing the patient to use the
e. Capillary telangiectasia affected limb
III.23. This magnetic resonance imaging (MRI) scan shows which type c. Resistance provided by stronger muscles is used to facilitate the
of vascular malformation? weaker components of the same motion pattern
a. Arteriovenous malformation d. Patient is initially constrained to bed for 2 weeks to allow the
b. Dural arteriovenous fistula brain to rest before initiation of intense therapy
c. Cavernous malformation e. Transcranial magnetic stimulation is used in combination with
d. Developmental venous anomaly constraining movement for intermittent periods
e. Capillary telangiectasia
Answers However, for cervical arterial dissection, the 2019 Stroke

guidelines states that “alteplase in acute ischemic stroke
III.1. Answer d. with known or suspected to be associated with extracranial
Approximately 30% to 40% of ischemic strokes are due to a cervical arterial dissection is reasonably safe within 4.5
cardioembolic cause, with atrial fibrillation being the most hours and probably recommended.” IV thrombolytics
common. should not be used in patients in whom the blood pressure
III.2. Answer a. is 185/110 mm Hg or higher despite treatment. If the blood
Carotid intervention is recommended for patients with pressure can be safely lowered below 185/110 mm Hg with
symptomatic internal carotid artery stenosis measuring 70% treatment, the patient could be a candidate for thrombolysis.
to 99% by noninvasive studies (MRA, CTA, or ultrasonogra- III.10. Answer e.
phy) or greater than 50% by cerebral angiography. Carotid There is no minimum NIHSS score in which IV thrombolyt-
intervention is not recommended early on for patients with ics should not be given. Patients with isolated gait ataxia,
severe deficit because of the risk of reperfusion injury. for example, may have a disabling stroke but have an
Carotid intervention in the clinical setting of asymptomatic NIHSS score of 0. The 2019 American Heart/Stroke
disease is a matter of debate for patients with internal carotid Association guidelines suggest that IV thrombolytics are
artery stenosis greater than 60%. If the internal carotid artery reasonable if the NIHSS score is less than 5 AND there is
stenosis is asymptomatic and less than 60%, medical man- disability due to the deficit. IV thrombolytics are not rec-
agement is generally indicated. ommended if the NIHSS score is less than 5 and the deficits
III.3. Answer d. are considered nondisabling. Clinical judgment of the dis-
Direct oral anticoagulants are reasonable alternatives to war- ability caused by the stroke should be used to make deci-
farin for patients with nonvalvular atrial fibrillation, for sions about IV thrombolytics.
stroke prevention. The Watchman Left Atrial Appendage III.11. Answer d.
Closure Device (Boston Scientific Corp) is also a reasonable This patient is within 6 hours of symptom onset with a nor-
alternative if a patient has a high risk of systemic bleeding. mal Alberta Stroke Program Early Computed Tomography
However, patients must be taking an antithrombotic—and Score (ASPECTS) and an M1 occlusion. Further imaging is
usually an anticoagulant agent—for the first several weeks not helpful. The patient should be taken immediately to the
after device placement. endovascular suite for clot retrieval.
III.4. Answer c. III.12. Answer c.
The anterior choroidal artery branches from the internal Patients presenting at more than 6 hours after last known
carotid artery and supplies the ipsilateral posterior limb of normal may benefit from the use of advanced imaging to
the internal capsule of the thalamus, including the lateral determine whether there is penumbra to save. CT perfusion
geniculate body, piriform cortex, caudate tail, and part of the and MRI diffusion are acceptable options. If a penumbra is
hippocampus and amygdala. found, endovascular therapy could be performed. Emerging
III.5. Answer b. data are evaluating the safety of IV r-tPA in this patient
A pure sensory stroke generally localizes to the contralateral group.
thalamus and particularly the ventral posterolateral and III.13. Answer d.
ventral posteromedial aspects of the thalamus, where sen- The CHA2DS2- VASc abbreviation stands for congestive
sory fibers synapse. heart failure, hypertension, age 75 years or older, diabetes
III.6. Answer b. mellitus, stroke or transient ischemic attack or thromboem-
The patient is presenting with a history and imaging find- bolism, vascular disease, age 65 to 74 years, and sex cate-
ings most suggestive of cerebral autosomal dominant arteri- gory (female).
opathy with subcortical infarcts and leukoencephalopathy, a III.14. Answer c.
condition secondary to a missense mutation in the Notch3 Hypertension is an important risk factor for ischemic stroke
gene. and intracerebral hemorrhage. It has the highest popula-
III.7. Answer d. tion-attributable risk of the common risk factors.
The patient most likely has Sneddon syndrome, a nonin- III.15. Answer d.
flammatory vasculopathy that presents with cerebral isch- Because DOACs are excreted renally and dose adjustments
emia, seizures, dementia, and a lacelike skin rash (livedo are necessary, kidney function should be monitored at least
reticularis). Sneddon syndrome also may be associated with annually. Antifactor Xa level is not routinely monitored, but
antiphospholipid syndrome. in the event of a patient having recurrent thromboembolism
III.8. Answer c. despite taking a DOAC, testing for it may prove useful.
The patient is presenting with a progressive headache that III.16. Answer d.
acutely worsened and signs of increased intracranial pressure According to the 2017 American College of Cardiology
(ie, papilledema, cranial nerve VI palsy, and visual obscura- Treatment for Hypertension Guidelines, the target blood
tions). Her presentation is most likely secondary to a cerebral pressure for patients who have had an ischemic stroke is
venous sinus thrombosis. The postpartum period is a risk fac- 130/80 mm Hg. However, the statement recommends initi-
tor for cerebral venous sinus thrombosis formation, given the ating treatment when the blood pressure is greater than
substantial hormonal changes and fluid shifts, which ulti- 140/90 mm Hg.
mately result in a hypercoagulable state. An MRV would be the III.17. Answer a.
best study to evaluate for a cerebral venous sinus thrombosis. The most common cause of hemorrhage is hypertension.
III.9. Answer c. The basal ganglia location also points toward a hyperten-
For patients with suspected endocarditis, risk of bleeding is sive hemorrhage.
increased and IV thrombolytics would be contraindicated. III.18. Answer e.
Patients who have ischemic stroke due to aortic dissection Corticosteroid use is generally not effective for improving
may have increased risk of bleeding into the dissected artery, outcome from intracerebral hemorrhage. In selected cir-
and IV thrombolytics would generally be contraindicated. cumstances, corticosteroids may be used in the clinical
Questions and Answers 449
setting of vasogenic edema associated with a hemorrhagic SUGGESTED READING

neoplasm.
III.19. Answer b. Barrett KM, Meschia JF, editors. Stroke. 1st ed, Kindle Edition.
The ICH score is a simple, easy clinical grading scale for Hoboken (NJ): Wiley Blackwell; c2013. (NIP- Neurology in
predicting a 30-day mortality rate. Hunt-Hess and the WFNS Practice series.)
grading systems are used for subarachnoid hemorrhage. Brazis P, Masdeu JC, Biller J. Localization in clinical neurology.
III.20. Answer b. 7th ed. Philadelphia (PA): Wolters Kluwer; c2017. 713 p.
About 0.5% to 2% of the population has an unruptured Brown AW, Schultz BA. Recovery and rehabilitation after stroke.
intracranial saccular aneurysm. Semin Neurol. 2010 Nov;30(5):511–7. Epub 2011 Jan 4.
III.21. Answer c. Caplan L. Uncommon causes of stroke. 3rd ed. Cambridge (UK):
The most important factors are increasing size and poste- Cambridge University Press; c2018.
rior circulation or posterior communicating artery segment Caplan LR. Caplan’s stroke: a clinical approach. 5th ed. Cambridge
location. Polycystic kidney disease and fibromuscular dys- (UK): Cambridge University Press; c2016. 640 p.
plasia increase the likelihood of an aneurysm developing Flemming KD, Lanzino G. Management of unruptured intracranial
but not necessarily the risk of rupture. Age, hypertension, aneurysms and cerebrovascular malformations. Continuum
Finnish or Japanese heritage, and prior subarachnoid hem- (Minneap Minn). 2017 Feb;23(1, Cerebrovascular
orrhage increase this risk. Disease):181–210.
III.22. Answer c. Krassioukov A, Warburton DE, Teasell R, Eng JJ; Spinal Cord Injury
Cavernous malformations of the brain may be sporadic or Rehabilitation Evidence Research Team. A systematic review of
familial. The KRIT1 mutation, or CCM1, is the most com- the management of autonomic dysreflexia after spinal cord
mon type of the familial form. Cases of familial arteriove- injury. Arch Phys Med Rehabil. 2009 Apr;90(4):682–95.
nous malformation occur, but these are rare. Lo WD, Kumar R. Arterial ischemic stroke in children and young
III.23. Answer d. adults. Continuum (Minneap Minn). 2017 Feb;23(1,
This axial T1 MRI with contrast medium shows a large Cerebrovascular Disease):158–80.
developmental venous anomaly in the right cerebellum. Majersik JJ. Inherited and uncommon causes of stroke. Continuum
III.24. Answer b. (Minneap Minn). 2017 Feb;23(1, Cerebrovascular Disease):211–37.
The spasticity associated with ischemic stroke is often O’Carroll CB, Barrett KM. Cardioembolic stroke. Continuum
treated with baclofen, tizanidine, diazepam, and dantrolene. (Minneap Minn). 2017 Feb;23(1, Cerebrovascular Disease):111–32.
III.25. Answer a. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis
Autonomic dysreflexia affects patients who have an injury NC, Becker K, et al. Guidelines for the early management of
at T6 or above. This results in an uninhibited sympathetic patients with acute ischemic stroke: 2019 update to the 2018
response to noxious stimuli. Symptoms typically include Guidelines for the Early Management of Acute Ischemic
headache, blood pressure higher than baseline, diaphore- Stroke: A Guideline for Healthcare Professionals From the
sis, facial flushing, pupillary dilatation, and bradycardia. American Heart Association/American Stroke Association.
III.26. Answer b. Stroke. 2019 Dec;50(12):e344-e418. Epub 2019 Oct 30. Erratum
Constraint-induced movement therapy involves restraint of in: Stroke. 2019 Dec;50(12):e440-1.
the unaffected limb, effectively forcing the use of the Zalewski NL, Rabinstein AA, Krecke KN, Brown RD Jr, Wijdicks
affected limb in intensive motor shaping and repetitive task EFM, Weinshenker BG, et al. Characteristics of spontaneous
practice directed by a clinician. spinal cord infarction and proposed diagnostic criteria. JAMA
Neurol. 2019 Jan 1;76(1):56–63.

Mayo Clinic Neurology Board Review - (Section III Cerebrovascular Disorders)

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Mayo Clinic Neurology Board Review - (Section III Cerebrovascular Disorders)

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Section

Introduction Overview of Ischemic Stroke

Table 48.1. Vascular brainstem syndromes are described

Table 48.1 • Large-​Vessel Clinical Syndromes

Internal carotid artery Ipsilateral retinal ischemia (amaurosis)

Superior cerebellar artery Ipsilateral ataxia

Table 48.2 • Brainstem Clinical Syndromes

this type of stroke.

Table 48.3 • Lacunar Syndromes

modifiable risk factors, 3) monitor for stroke-​related compli-

Imaging of the extracranial and intracranial arteries

Cardiac disorder Radiation induced

Behçet syndrome Other

Box 48.3 • Mimics of Cerebral Ischemia

Emergency department evaluation

Consider brain MRI

Anterior circulation Posterior circulation

Extracranial carotid studya

AP (vs AC) AP CEA/CAS For selected Abnormal CXR or High suspicion

Treat Prolonged cardiac

partial thromboplastin time; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography.

The intimal tear results in a false lumen, and occasionally

Table 48.4 • CHADS2 Score A B

History of congestive heart failure 1

Table 48.5 • Stroke Risk per 100 Person-​years

0 0.25 0.49 417

with permission of Mayo Foundation for Medical Education and

Figure 48.6 Fibromuscular Dysplasia. Appearance of severe

Figure 48.5 Magnetic Resonance Angiography of Carotid

moyamoya disease has not been determined, but the dis-

Infectious arteritis is rare. It has been associated with Coagulation Disorders

unexplained thrombotic events, an unexplained prolon-

Introduction clinically by migraine, stroke, mood disturbances, and

Cerebral Autosomal Dominant Arteriopathy ron signs.

Table 49.1 • Genetic Causes of Cerebral Ischemia

CADASIL syndrome Autosomal dominant Migraine

Neurovascular imaging may show dilatation or dolichoec-

Mitochondrial Myopathy, Encephalopathy, • CADASIL syndrome is an autosomal dominant

stroke-​like episodes in their 40s to 60s, followed by Special Situations in Stroke

One-​half occur within the first 24 hours and 90% within

• Perinatal stroke is generally defined as any

Cogan syndrome Interstitial keratitis or scleritis Clinical picture Immunosuppressants

Figure 49.4 Periventricular-​Intraventricular Hemorrhage. A, Coronal section shows a typical periventricular-​intraventricular

with an anterior spinal artery syndrome; posterior spinal

Cardiac disorders Hypercoagulable states

Dissection MERRF syndrome, Kearns-​Sayre syndrome)

potential during aortic surgery and the avoidance of

Decreased • Patients with spinal cord infarction typically present

infarction, or hemorrhage occurs.

Subarachnoid 5–​20 per 100,000 Aneurysm More common during

Box 49.3 • Proposed Criteria for SCI Diagnosis and

angiography, aortic surgery, surgical 3. Cerebrospinal fluid

Abbreviations: h, hour; SCI, spinal cord infarction.

Table 49.6 • Risk Factors for Cerebral Venous Sinus A

General disorder Dehydration

identified, anticoagulation is generally recommended for 3

• Patients with venous thrombosis typically present

911 call and EMS transport

Emergency department evaluation STAT

Yes Manage per

Administer Yes No Suspicion that

Suspicion that Yes STAT head and Yes No Admit to

Admit to Large-vessel No Admit to

Table 48.1 • Large-Vessel Clinical Syndromes

Table 48.2 • Brainstem Clinical Syndromes

Table 48.3 • Lacunar Syndromes

modifiable risk factors, 3) monitor for stroke-related compli-

Table 48.4 • CHADS2 Score A B

Table 48.5 • Stroke Risk per 100 Person-years

Table 49.1 • Genetic Causes of Cerebral Ischemia

stroke-like episodes in their 40s to 60s, followed by Special Situations in Stroke

One-half occur within the first 24 hours and 90% within

Figure 49.4 Periventricular-Intraventricular Hemorrhage. A, Coronal section shows a typical periventricular-intraventricular

Dissection MERRF syndrome, Kearns-Sayre syndrome)

Subarachnoid 5–20 per 100,000 Aneurysm More common during

Table 49.6 • Risk Factors for Cerebral Venous Sinus A

Introduction to 30 days. However, long-term use is generally not recom-

Box 51.1 • Indications for Antiplatelet or Table 51.1 • CHA2DS2-VASc Score

Box 51.2 • Reasons for Failure of Antiplatelet 0 0.0 (0.0-0.0)

Table 51.3 • Characteristics of the Direct Oral Anticoagulants

Table 51.4 • Comparison of Clinical Trials of the DOACs vs Vitamin K Antagonists

Figure 52.2 Hypertensive Intraparenchymal Cerebral Hemorrhage on Non–Contrast-Medium Computed Tomography. A,

Table 52.1 • Magnetic Resonance Imaging Characteristics of Intraparenchymal Cerebral

GCS scorea • A spot sign on post–contrast-medium CT is due to a

Location Group 1 Group 2 7–12 mm 13–24 mm ≥25 mm

Post-P comm (n = 445) 2.5% 3.4% 14.5% 18.4% 50%

• About 0.5%-2% of the US population have a UIA.

Table 53.3 • Genetics of CCM

Locus 7q11-q22 7p15-13 3q25.2-q27

Figure 53.7 Developmental Venous Anomaly. Coronal T1-

brain. Ipsilateral to the vascular malformation, a port-wine

Table 54.3 • Commonly Used Medications to Treat Spasticity