3350 PART 13 Neurologic Disorders

Thalamic hemorrhages also produce a contralateral hemiplegia or

hemiparesis from pressure on, or dissection into, the adjacent internal

capsule. A prominent sensory deficit involving all modalities is usually

present. Aphasia, often with preserved verbal repetition, may occur

after hemorrhage into the dominant thalamus, and constructional

apraxia or mutism occurs in some cases of nondominant hemorrhage. There may also be a homonymous visual field defect. Thalamic

hemorrhages cause several typical ocular disturbances by extension

inferiorly into the upper midbrain. These include deviation of the eyes

downward and inward so that they appear to be looking at the nose,

unequal pupils with absence of light reaction, skew deviation with the

eye opposite the hemorrhage displaced downward and medially, ipsilateral Horner’s syndrome, absence of convergence, paralysis of vertical

gaze, and retraction nystagmus. Patients may later develop a chronic,

contralateral pain syndrome (Déjérine-Roussy syndrome).

In pontine hemorrhages, deep coma with quadriplegia often occurs

over a few minutes. Typically, there is prominent decerebrate rigidity

and “pinpoint” (1 mm) pupils that react to light. There is impairment

of reflex horizontal eye movements evoked by head turning (doll’shead or oculocephalic maneuver) or by irrigation of the ears with ice

water (Chap. 28). Hyperpnea, severe hypertension, and hyperhidrosis

are common. Most patients with deep coma from pontine hemorrhage

ultimately die or develop a locked-in state, but small hemorrhages are

compatible with survival and significant recovery.

Cerebellar hemorrhages usually develop over several hours and are

characterized by occipital headache, repeated vomiting, and ataxia of

gait. In mild cases, there may be no other neurologic signs except for

gait ataxia. Dizziness or vertigo may be prominent. There is often paresis of conjugate lateral gaze toward the side of the hemorrhage, forced

deviation of the eyes to the opposite side, or an ipsilateral sixth nerve

palsy. Less frequent ocular signs include blepharospasm, involuntary

closure of one eye, ocular bobbing, and skew deviation. Dysarthria and

dysphagia may occur. As the hours pass, the patient often becomes stuporous and then comatose from brainstem compression or obstructive

hydrocephalus; immediate surgical evacuation before severe brainstem

compression occurs may be lifesaving. Hydrocephalus from fourth

ventricle compression can be relieved by external ventricular drainage;

however, in this situation, definitive hematoma evacuation is recommended rather than treatment with ventricular drainage alone. If the

deep cerebellar nuclei are spared, full recovery is common.

Lobar Hemorrhage The major neurologic deficit with an occipital hemorrhage is hemianopsia; with a left temporal hemorrhage,

aphasia and delirium; with a parietal hemorrhage, hemisensory loss;

and with frontal hemorrhage, arm weakness. Large hemorrhages may

be associated with stupor or coma if they compress the thalamus or

midbrain. Most patients with lobar hemorrhages have focal headaches,

and more than one-half vomit or are drowsy. Stiff neck and seizures

are uncommon.

Other Causes of ICH CAA is a disease of the elderly in which

arteriolar degeneration occurs and amyloid is deposited in the walls

of the cerebral arteries. Amyloid angiopathy causes both single and

recurrent lobar hemorrhages and is probably the most common cause

of lobar hemorrhage in the elderly. It accounts for some intracranial

hemorrhages associated with IV thrombolysis given for myocardial

infarction. This disorder can be suspected in patients who present with

multiple hemorrhages (and infarcts) over several months or years or in

patients with “microbleeds” in the cortex, seen on brain MRI sequences

sensitive for hemosiderin (iron-sensitive imaging), but it is definitively diagnosed by pathologic demonstration of Congo red staining

of amyloid in cerebral vessels. The ε2 and ε4 allelic variations of the

apolipoprotein E gene are associated with increased risk of recurrent

lobar hemorrhage and may therefore be markers of amyloid angiopathy. Positron emission tomography imaging can image amyloid-beta

deposits in CAA using specific antibody labels and may be helpful in

diagnosing CAA noninvasively. Although cerebral biopsy is the most

definitive method of diagnosis, evidence of inflammation on lumbar

puncture should prompt consideration of CAA-associated vasculitis

as an underlying cause, and oral glucocorticoids may be beneficial.

Noninflammatory CAA has no specific treatment. Oral anticoagulants

are typically avoided.

Cocaine and methamphetamine are frequent causes of stroke in

young (age <45 years) patients. ICH, ischemic stroke, and subarachnoid hemorrhage (SAH) are all associated with stimulant use. Angiographic findings vary from completely normal arteries to large-vessel

occlusion or stenosis, vasospasm, or changes consistent with vasculopathy. The mechanism of sympathomimetic-related stroke is not known,

but cocaine enhances sympathetic activity causing acute, sometimes

severe, hypertension, and this may lead to hemorrhage. Slightly

more than one-half of stimulant-related intracranial hemorrhages are

intracerebral and the rest are subarachnoid. In cases of SAH, a saccular

aneurysm is usually identified. Presumably, acute hypertension causes

aneurysmal rupture.

Head injury often causes intracranial bleeding. The common sites

are intraparenchymal (especially temporal and inferior frontal lobes)

and into the subarachnoid, subdural, and epidural spaces. Trauma

must be considered in any patient with an unexplained acute neurologic deficit (hemiparesis, stupor, or confusion), particularly if the

deficit occurred in the context of a fall (Chap. 443).

Intracranial hemorrhages associated with anticoagulant therapy

can occur at any location; they are often lobar or subdural. Anticoagulant-related ICHs may continue to evolve over 24–48 h, especially if

coagulopathy is insufficiently reversed. Coagulopathy and thrombocytopenia should be reversed rapidly, as discussed below. ICH associated

with hematologic disorders (leukemia, aplastic anemia, thrombocytopenic purpura) can occur at any site and may present as multiple

ICHs. Skin and mucous membrane bleeding may be evident and offers

a diagnostic clue.

Hemorrhage into a brain tumor may be the first manifestation of

neoplasm. Choriocarcinoma, malignant melanoma, renal cell carcinoma, and bronchogenic carcinoma are among the most common

metastatic tumors associated with ICH. Glioblastoma multiforme in

adults and medulloblastoma in children may also have areas of ICH.

Hypertensive encephalopathy is a complication of malignant hypertension. In this acute syndrome, severe hypertension is associated with

headache, nausea, vomiting, convulsions, confusion, stupor, and coma.

Focal or lateralizing neurologic signs, either transitory or permanent,

may occur but are infrequent and therefore suggest some other vascular disease (hemorrhage, embolism, or atherosclerotic thrombosis).

There are retinal hemorrhages, exudates, papilledema (hypertensive

retinopathy), and evidence of renal and cardiac disease. In most cases,

ICP and CSF protein levels are elevated. MRI brain imaging shows a

pattern of typically posterior (occipital > frontal) brain edema that is

reversible and termed reversible posterior leukoencephalopathy. The

hypertension may be essential or due to chronic renal disease, acute

glomerulonephritis, acute toxemia of pregnancy, pheochromocytoma,

or other causes. Lowering the blood pressure reverses the process, but

stroke can occur, especially if blood pressure is lowered too rapidly.

Neuropathologic examination reveals multifocal to diffuse cerebral

edema and hemorrhages of various sizes from petechial to massive.

Microscopically, there is necrosis of arterioles, minute cerebral infarcts,

and hemorrhages. The term hypertensive encephalopathy should be

reserved for this syndrome and not for chronic recurrent headaches,

dizziness, recurrent transient ischemic attacks, or small strokes that

often occur in association with high blood pressure. Distinguishing

hypertensive encephalopathy with ICH from hypertensive ICH is

important since aggressive lowering of SBP to 140–180 mmHg acutely

is usually considered in hypertensive ICH, but less aggressive measures

should be used in hypertensive encephalopathy. Having no alteration

in mental status or other prodrome prior to the ICH favors hypertensive ICH as the disease.

Primary intraventricular hemorrhage is rare and should prompt

investigation for an underlying vascular anomaly. Sometimes bleeding begins within the periventricular substance of the brain and

dissects into the ventricular system without leaving signs of intraparenchymal hemorrhage. Alternatively, bleeding can arise from

periependymal veins. Vasculitis, usually polyarteritis nodosa or lupus

3351 Intracranial Hemorrhage CHAPTER 428

erythematosus, can produce hemorrhage in any region of the central

nervous system; most hemorrhages are associated with hypertension,

but the arteritis itself may cause bleeding by disrupting the vessel

wall. Nearly one-half of patients with primary intraventricular hemorrhage have identifiable bleeding sources seen using conventional

angiography.

Venous sinus thrombosis (Chap. 427) causes cortical vein hypertension, cerebral edema, and venous infarction. This may progress to

cause ICH surrounding the region of the occluded cerebral venous

sinus or within the drainage region of the vein of Labbé, producing a

posterior temporal inferior parietal hematoma. Despite the presence of

hemorrhage, IV anticoagulation is helpful to reduce the venous hypertension and limit venous ischemia and further ICH.

Sepsis can cause small petechial hemorrhages throughout the cerebral white matter. Moyamoya disease (Chap. 427), mainly an occlusive

arterial disease that causes ischemic symptoms, may on occasion

produce ICH, particularly in the young. Hemorrhages into the spinal

cord are usually the result of an AVM, cavernous malformation, or

metastatic tumor. Epidural spinal hemorrhage produces a rapidly evolving syndrome of spinal cord or nerve root compression (Chap. 442).

Spinal hemorrhages usually present with sudden back pain and some

manifestation of myelopathy.

Laboratory and Imaging Evaluation Patients should have routine blood chemistries and hematologic studies. Specific attention to

the platelet count, prothrombin time, partial thromboplastin time, and

international normalized ratio is important to identify coagulopathy.

CT imaging reliably detects acute focal hemorrhages in the supratentorial space. Rarely, very small pontine or medullary hemorrhages may

not be well delineated because of motion and bone-induced artifact

that obscure structures in the posterior fossa. After the first 2 weeks,

x-ray attenuation values of clotted blood diminish until they become

isodense with surrounding brain. Mass effect and edema may remain.

In some cases, a surrounding rim of contrast enhancement appears

after 2–4 weeks and may persist for months. MRI, although more sensitive for delineating posterior fossa lesions, is generally not necessary for

primary diagnosis. Images of flowing blood on MRI scan may identify

AVMs as the cause of the hemorrhage. MRI, CT angiography (CTA),

and conventional x-ray angiography are used when the cause of intracranial hemorrhage is uncertain, particularly if the patient is young

or not hypertensive and the hematoma is not in one of the usual sites

for hypertensive hemorrhage. CTA or postcontrast CT imaging may

reveal one or more small areas of enhancement within a hematoma;

this “spot sign” is thought to represent ongoing bleeding. The presence

of a spot sign is associated with an increased risk of hematoma expansion, increased mortality, and lower likelihood of favorable functional

outcome. Because patients typically have focal neurologic signs and

obtundation and often show signs of increased ICP, a lumbar puncture

is generally unnecessary and should usually be avoided because it may

induce cerebral herniation.

TREATMENT

Intracerebral Hemorrhage

ACUTE MANAGEMENT

After immediate attention to blood pressure and airway protection

(see above), focus can switch to medical and surgical management.

Approximately 40% of patients with a hypertensive ICH die, but

survivors can have a good to complete recovery. The ICH Score

(Table 428-2) is a validated clinical grading scale that is useful for

stratification of mortality risk and clinical outcome. However, a specific ICH clinical grading scale should not be used to precisely prognosticate outcome because of the concern of creating a self-fulfilling

prophecy of poor outcome if early aggressive care is withheld. Any

identified coagulopathy should be corrected as soon as possible. For

patients taking vitamin K antagonists (VKAs), rapid correction of

coagulopathy can be achieved by infusing prothrombin complex concentrates (PCCs), which can be administered quickly, with vitamin

K administered concurrently. Fresh frozen plasma (FFP) is an alternative, but since it requires larger fluid volumes and longer time to

achieve adequate reversal than PCC, it is not recommended if PCC

is available. Idarucizumab is a monoclonal antibody to dabigatran,

and the administration of two doses reverses the anticoagulation

effect of dabigatran quickly. The oral Xa inhibitors apixaban and

rivaroxaban can be reversed with andexanet alfa. PCC may partially

reverse the effects of oral factor Xa inhibitors and are reasonable to

administer if andexanet alfa is not available. When ICH is associated

with thrombocytopenia (platelet count <50,000/μL), transfusion of

fresh platelets is indicated. A clinical trial of platelet transfusions in

patients with ICH and without thrombocytopenia who were taking

antiplatelet drugs showed no benefit and possible harm.

Hematomas may expand for several hours following the initial

hemorrhage, even in patients without coagulopathy. The precise

mechanism is unclear. A phase 3 trial of treatment with recombinant factor VIIa reduced hematoma expansion; however, clinical

outcomes were not improved, so use of this drug is not recommended. Blood pressure lowering has been considered due to the

theoretical risk of acutely elevated blood pressure on hematoma

expansion, although clinical trials did not find a difference in

hematoma expansion between the SBP targets of 140–180 mmHg.

In deep hemorrhages that involve the basal ganglia, more intensive

blood pressure lowering reduced hematoma expansion but had no

effect on functional outcome.

Evacuation of supratentorial hematomas does not appear to

improve outcome for most patients. The International Surgical

Trial in Intracerebral Haemorrhage (STICH) randomized patients

with supratentorial ICH to either early surgical evacuation or

initial medical management. No benefit was found in the early

surgery arm, although analysis was complicated by the fact that

26% of patients in the initial medical management group ultimately

had surgery for neurologic deterioration. The follow-up study,

STICH-II, found that surgery within 24 h of lobar supratentorial

hemorrhage did not improve overall outcome but might have a role

in select severely affected patients. Therefore, existing data do not

support routine surgical evacuation of supratentorial hemorrhages

in stable patients. However, many centers still consider surgery for

patients deemed salvageable and who are experiencing progressive

neurologic deterioration due to herniation. Surgical techniques

continue to evolve. A minimally invasive endoscopic hematoma

evacuation followed by thrombolysis with the aim of decreasing clot

TABLE 428-2 The ICH Score

CLINICAL OR IMAGING FACTOR POINT SCORE

Age

<80 years 0

≥80 years 1

Hematoma Volume

<30 cc 0

≥30 cc 1

Intraventricular Hemorrhage Present

No 0

Yes 1

Infratentorial Origin of Hemorrhage

No 0

Yes 1

Glasgow Coma Scale Score

13–15 0

5–12 1

3–4 2

Total Score 0–6 Sum of each category above

Source: Reproduced with permission from JC Hemphill 3rd et al: The ICH score:

A simple, reliable grading scale for intracerebral hemorrhage. Stroke 32:891,

2001.

3352 PART 13 Neurologic Disorders

size has not been shown to improve outcome in clinical trials. The

administration of tranexamic acid was not found to alter outcome

in a large randomized trial.

For cerebellar hemorrhages, a neurosurgeon should be consulted

immediately to assist with the evaluation; most cerebellar hematomas >3 cm in diameter will require surgical evacuation. If the

patient is alert without focal brainstem signs and if the hematoma is

<1 cm in diameter, surgical removal is usually unnecessary. Patients

with hematomas between 1 and 3 cm require careful observation

for signs of impaired consciousness, progressive hydrocephalus,

and precipitous respiratory failure. Hydrocephalus due to cerebellar

hematoma requires surgical evacuation and should not be treated

solely with ventricular drainage.

Tissue surrounding hematomas is displaced and compressed but

not necessarily infarcted. Hence, in survivors, major improvement

commonly occurs as the hematoma is reabsorbed and the adjacent

tissue regains its function. Careful management of the patient

during the acute phase of the hemorrhage can lead to considerable

recovery.

Surprisingly, ICP is often normal even with large ICHs. However,

if the hematoma causes marked midline shift of structures with

consequent obtundation, coma, or hydrocephalus, osmotic agents

can be instituted in preparation for placement of a ventriculostomy

or parenchymal ICP monitor (Chap. 307). Once ICP is recorded,

CSF drainage (if available), osmotic therapy, and blood pressure

management can be tailored to maintain cerebral perfusion pressure (MAP minus ICP) at least 50–70 mmHg. For example, if ICP

is found to be high, CSF can be drained from the ventricular space

and osmotic therapy continued; persistent or progressive elevation

in ICP may prompt surgical evacuation of the clot. Alternately,

if ICP is normal or only mildly elevated, interventions such as

osmotic therapy may be tapered. Because hyperventilation may

actually produce ischemia by cerebral vasoconstriction, induced

hyperventilation should be limited to acute resuscitation of the

patient with presumptive high ICP and eliminated once other

treatments (osmotic therapy or surgical treatments) have been

instituted. Glucocorticoids are not helpful for the edema from

intracerebral hematoma.

PREVENTION

Hypertension is the leading cause of primary ICH. Prevention is

aimed at reducing chronic hypertension, eliminating excessive

alcohol use, and discontinuing use of illicit drugs such as cocaine

and amphetamines. Current guidelines recommend that patients

with CAA should generally avoid oral anticoagulant medications,

but antiplatelet agents may be administered if there is an indication

based on atherothrombotic vascular disease.

VASCULAR ANOMALIES

Vascular anomalies can be divided into congenital vascular malformations and acquired vascular lesions.

■ CONGENITAL VASCULAR MALFORMATIONS

True AVMs, venous anomalies, and capillary telangiectasias are lesions

that usually remain clinically silent through life. AVMs are probably

congenital, but cases of acquired lesions have been reported.

True AVMs are congenital shunts between the arterial and venous

systems that may present with headache, seizures, and intracranial

hemorrhage. AVMs consist of a tangle of abnormal vessels across the

cortical surface or deep within the brain substance. AVMs vary in size

from a small blemish a few millimeters in diameter to a large mass

of tortuous channels composing an arteriovenous shunt of sufficient

magnitude to raise cardiac output and precipitate heart failure. Blood

vessels forming the tangle interposed between arteries and veins are

usually abnormally thin and histologically resemble both arteries and

veins. AVMs occur in all parts of the cerebral hemispheres, brainstem,

and spinal cord, but the largest ones are most frequently located in the

posterior half of the hemispheres, commonly forming a wedge-shaped

lesion extending from the cortex to the ventricle.

Bleeding, headache, and seizures are most common between the

ages of 10 and 30, occasionally as late as the fifties. AVMs are more

frequent in men, and rare familial cases have been described. Familial

AVM may be a part of the autosomal dominant syndrome of hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber) syndrome due

to mutations in either endoglin or activin receptor-like kinase 1,

both involved in transforming growth factor (TGF) signaling and

angiogenesis.

Headache (without bleeding) may be hemicranial and throbbing,

like migraine, or diffuse. Focal seizures, with or without generalization, occur in ~30% of cases. One-half of AVMs become evident

as ICHs. In most, the hemorrhage is mainly intraparenchymal with

extension into the subarachnoid space in some cases. Unlike primary SAHs (Chap. 429), blood from a ruptured AVM is usually not

deposited in the basal cisterns, and symptomatic cerebral vasospasm

is rare. The risk of AVM rupture is strongly influenced by a history of

prior rupture. Although unruptured AVMs have a hemorrhage rate of

~2–4% per year, previously ruptured AVMs may have a rate as high

as 17% a year, at least for the first year. Hemorrhages may be massive,

leading to death, or may be as small as 1 cm in diameter, leading to

minor focal symptoms or no deficit. The AVM may be large enough

to steal blood away from adjacent normal brain tissue or to increase

venous pressure significantly to produce venous ischemia locally and

in remote areas of the brain. This is seen most often with large AVMs

in the territory of the middle cerebral artery.

Large AVMs of the anterior circulation may be associated with a systolic and diastolic bruit (sometimes self-audible) over the eye, forehead,

or neck and a bounding carotid pulse. Headache at the onset of AVM

rupture is generally not as explosive as with aneurysmal rupture. MRI

is better than CT for diagnosis, although noncontrast CT scanning

sometimes detects calcification of the AVM and contrast may demonstrate the abnormal blood vessels. Once identified, conventional x-ray

angiography is the gold standard for evaluating the precise anatomy of

the AVM.

Surgical treatment of AVMs presenting with hemorrhage, often

done in conjunction with preoperative embolization to reduce operative bleeding, is usually indicated for accessible lesions. Stereotactic

radiosurgery, an alternative to conventional surgery, can produce a

slow sclerosis of the AVM over 2–3 years.

Several angiographic features can be used to help predict future

bleeding risk. Paradoxically, smaller lesions seem to have a higher

hemorrhage rate. The presence of deep venous drainage, venous outflow stenosis, and intranidal aneurysms may increase rupture risk.

Because of the relatively low annual rate of hemorrhage and the risk

of complications due to surgical or endovascular treatment, the indications for surgery in asymptomatic AVMs are uncertain. The ARUBA

(A Randomized Trial of Unruptured Brain Arteriovenous Malformations) trial randomized patients to medical management versus intervention (surgery, endovascular embolization, combination

embolization and surgery, or gamma-knife). The trial was stopped

prematurely for harm, with the medical arm achieving the combined

endpoint of death or symptomatic stroke in 10% of patients compared to 31% in the intervention group at a mean follow-up time of

33 months. This highly significant finding argues against routine intervention for patients presenting without hemorrhage, although debate

ensues regarding the generalizability of these results.

Venous anomalies are the result of development of anomalous cerebral, cerebellar, or brainstem venous drainage. These structures, unlike

AVMs, are functional venous channels. They are of little clinical significance and should be ignored if found incidentally on brain imaging

studies. Surgical resection of these anomalies may result in venous

infarction and hemorrhage. Venous anomalies may be associated with

cavernous malformations (see below), which do carry some bleeding

risk.

3353 Subarachnoid Hemorrhage CHAPTER 429

Capillary telangiectasias are true capillary malformations that often

form extensive vascular networks through an otherwise normal

brain structure. The pons and deep cerebral white matter are typical

locations, and these capillary malformations can be seen in patients

with hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber) syndrome. If bleeding does occur, it rarely produces mass effect or significant symptoms. No treatment options exist.

■ ACQUIRED VASCULAR LESIONS

Cavernous angiomas (cavernous malformations) are tufts of capillary

sinusoids that form within the deep hemispheric white matter and

brainstem with no normal intervening neural structures. The pathogenesis is unclear. Familial cavernous angiomas have been mapped to

several different genes: KRIT1, CCM2, and PDCD10. Both KRIT1 and

CCM2 have roles in blood vessel formation, whereas PDCD10 is an

apoptotic gene. Cavernous angiomas are typically <1 cm in diameter

and are often associated with a venous anomaly. Bleeding is usually of

small volume, causing slight mass effect only. The bleeding risk for single cavernous malformations is 0.7–1.5% per year and may be higher

for patients with prior clinical hemorrhage or multiple malformations.

Seizures may occur if the malformation is located near the cerebral

cortex. Surgical resection eliminates bleeding risk and may reduce seizure risk, but it is usually reserved for those malformations that form

near the brain surface. Radiation treatment has not been shown to be

of benefit. Recent retrospective data show that intracranial hemorrhage

from cavernous malformations is likely not increased with administration of antiplatelet and anticoagulant medications prescribed for other

medical conditions.

Dural arteriovenous fistulas are acquired connections usually

from a dural artery to a dural sinus. Patients may complain of a

pulse-synchronous cephalic bruit (“pulsatile tinnitus”) and headache.

Depending on the magnitude of the shunt, venous pressures may rise

high enough to cause cortical ischemia or venous hypertension and

hemorrhage, particularly SAH. Surgical and endovascular techniques

are usually curative. These fistulas may form because of trauma, but

most are idiopathic. There is an association between fistulas and dural

sinus thrombosis. Fistulas have been observed to appear months to

years following venous sinus thrombosis, suggesting that angiogenesis

factors elaborated from the thrombotic process may cause these anomalous connections to form. Alternatively, dural arteriovenous fistulas

can produce venous sinus occlusion over time, perhaps from the high

pressure and high flow through a venous structure.

■ FURTHER READING

Anderson CS et al: Rapid blood-pressure lowering in patients with

acute intracerebral hemorrhage. N Engl J Med 368:2355, 2013.

Christensen H et al: European stroke organization guideline on

reversal of oral anticoagulants in acute intracerebral hemorrhage.

Euro Stroke J 4:294, 2019.

Frontera J et al: Guideline for reversal of antithrombotics in intracranial hemorrhage. A statement for healthcare professionals from

the Neurocritical Care Society and Society of Critical Care Medicine.

Neurocrit Care 24:6, 2016.

Hemphill JC et al: Guidelines for the management of spontaneous

intracerebral hemorrhage: A guideline for healthcare professionals

from the American Heart Association/American Stroke Association.

Stroke 46:2032, 2015.

Mohr JP et al: Medical management with or without interventional therapy for unruptured brain arteriovenous malformations

(ARUBA): A multicentre, non-blinded, randomised trial. Lancet

383:614, 2014.

Steiner T et al: European Stroke Organisation (ESO) guidelines for

the management of spontaneous intracerebral hemorrhage. Int J

Stroke 9:840, 2014.

Subarachnoid hemorrhage (SAH) renders the brain critically ill from

both primary and secondary brain insults. Excluding head trauma, the

most common cause of SAH is rupture of a saccular aneurysm. Other

causes include bleeding from a vascular malformation (arteriovenous

malformation or dural arteriovenous fistula) and extension into the

subarachnoid space from a primary intracerebral hemorrhage. Some

idiopathic SAHs are localized to the perimesencephalic cisterns and

are benign; they probably have a venous or capillary source, and angiography is unrevealing.

■ SACCULAR (“BERRY”) ANEURYSM

Autopsy and angiography studies have found that ~2% of adults harbor

intracranial aneurysms, for a prevalence of 4 million persons in the

United States; the aneurysm will rupture, producing SAH, in 25,000–

30,000 cases per year. The overall mortality rate for aneurysmal SAH is

~35%, with around one-third of these patients dying immediately and

prior to hospital admission. Of those who survive, more than half are

left with clinically significant neurologic deficits as a result of the initial

hemorrhage, cerebral vasospasm with infarction, or hydrocephalus.

If the patient survives but the aneurysm is not obliterated, the rate of

rebleeding is ~20% in the first 2 weeks, 30% in the first month, and

~3% per year afterward. Given these alarming figures, the major therapeutic emphasis is on preventing the predictable early complications

of the SAH.

Unruptured, asymptomatic aneurysms are much less dangerous

than a recently ruptured aneurysm. The annual risk of rupture for

aneurysms <10 mm in size is ~0.1%, and for aneurysms ≥10 mm in size

is ~0.5–1%; the surgical morbidity rate far exceeds these percentages.

Aneurysm location may also factor into risk, with basilar bifurcation

aneurysms appearing to have a somewhat higher rupture risk. Because

of the longer length of exposure to risk of rupture, younger patients with

aneurysms >10 mm in size may benefit from prophylactic treatment. As

with the treatment of asymptomatic carotid stenosis, this risk-benefit

ratio strongly depends on the complication rate of treatment.

Giant aneurysms, those >2.5 cm in diameter, occur at the same

sites (see below) as small aneurysms, and account for 5% of cases. The

three most common locations are the terminal internal carotid artery,

middle cerebral artery (MCA) bifurcation, and top of the basilar artery.

Their risk of rupture is ~6% in the first year after identification and

may remain high indefinitely. They often cause symptoms by compressing the adjacent brain or cranial nerves.

Mycotic aneurysms are usually located distal to the first bifurcation of major arteries of the circle of Willis. Most result from infected

emboli due to bacterial endocarditis causing septic degeneration of

arteries and subsequent dilation and rupture. Whether these lesions

should be sought and repaired prior to rupture or left to heal spontaneously with antibiotic treatment remains controversial.

Pathophysiology Saccular aneurysms occur at the bifurcations

of the large- to medium-sized intracranial arteries; rupture is into

the subarachnoid space in the basal cisterns and sometimes into the

parenchyma of the adjacent brain. Approximately 85% of aneurysms

occur in the anterior circulation, mostly on the circle of Willis. About

20% of patients have multiple aneurysms, many at mirror sites bilaterally. As an aneurysm develops, it typically forms a neck with a dome.

The length of the neck and the size of the dome vary greatly and are

important factors in planning neurosurgical obliteration or endovascular embolization. The arterial internal elastic lamina disappears at

the base of the neck. The media thins, and connective tissue replaces

smooth-muscle cells. At the site of rupture (most often the dome), the

wall thins, and the tear that allows bleeding is often ≤0.5 mm long.

429 Subarachnoid Hemorrhage

J. Claude Hemphill, III,

Wade S. Smith, Daryl R. Gress

 

3346 PART 13 Neurologic Disorders

studies in individual patients taking aspirin is controversial because

of limited data.

In our practices, when considering antithrombotic therapy for

secondary stroke prevention for noncardioembolic strokes and

TIAs, we prescribe aspirin 81 mg/d in aspirin-naive patients after an

initial load of 325 mg. We add either clopidogrel (600-mg load, then

75 mg daily) or ticagrelor (180-mg load, then 90 mg twice daily)

for TIA or minor stroke (NIHSS <5) for 21–30 days, followed by

monotherapy with aspirin alone at 81 mg daily. We treat stroke due

to intracranial atherosclerosis with aspirin 81 mg plus clopidogrel

75 mg daily for 3 months, after which time treatment is continued

with aspirin alone.

ANTICOAGULATION THERAPY AND EMBOLIC

STROKE PREVENTION

Several trials have shown that anticoagulation (international normalized ratio [INR] range, 2–3) in patients with chronic nonvalvular (nonrheumatic) atrial fibrillation (NVAF) prevents cerebral

embolism and stroke and is safe. For primary prevention and for

patients who have experienced stroke or TIA, anticoagulation with

a vitamin K antagonist (VKA) reduces the risk by ~67%, which

clearly outweighs the 1–3% risk per year of a major bleeding complication. VKAs are difficult to dose, their effects vary with dietary

intake of vitamin K, and they require frequent blood monitoring

of the PTT/INR. Several newer oral anticoagulants (OACs) have

recently been shown to be more convenient and efficacious for

stroke prevention in NVAF. A randomized trial compared the oral

thrombin inhibitor dabigatran to VKAs in a noninferiority trial to

prevent stroke or systemic embolization in NVAF. Two doses of

dabigatran were used: 110 mg/d and 150 mg/d. Both dose tiers of

dabigatran were noninferior to VKAs in preventing second stroke

and systemic embolization, and the higher dose tier was superior (relative risk, 0.66; 95% CI, 0.53–0.82; p <.001) and the rate

of major bleeding was lower in the lower dose tier of dabigatran

compared to VKAs. Dabigatran requires no blood monitoring

to titrate the dose, and its effect is independent of oral intake of

vitamin K. Newer oral factor Xa inhibitors have also been found

to be equivalent or safer and more effective than VKAs in NVAF

stroke prevention. In the Apixaban for Reduction in Stroke and

Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE)

trial, patients were randomized between apixaban, 5 mg twice daily,

and dose-adjusted warfarin (INR 2–3). The combined endpoint of

ischemic or hemorrhagic stroke or system embolism occurred in

1.27% of patients in the apixaban group and in 1.6% in the warfarin

group (p <.001 for noninferiority and p <.01 for superiority). Major

bleeding was 1% less, favoring apixaban (p <.001). Similar results

were obtained in the Rivaroxaban Once Daily Oral Direct Factor Xa

Inhibition Compared with Vitamin K Antagonism for Prevention

of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF).

In this trial, patients with NVAF were randomized to rivaroxaban

versus warfarin: 1.7% of the factor Xa group and 2.2% of the warfarin group reached the endpoint of stroke and systemic embolism

(p <.001 for noninferiority); intracranial hemorrhage was also lower

with rivaroxaban. Finally, the factor Xa inhibitor edoxaban was also

found to be noninferior to warfarin. Thus, oral factor Xa inhibitors

are at least a suitable alternative to VKAs, for both primary and

secondary prevention, and likely are superior both in efficacy and

perhaps compliance. Recent FDA approval of a reversal agent for

the Xa inhibitors apixaban and rivaroxaban (andexanet alfa) provides an antidote in the case of major bleeding. Idarucizumab has

been available for reversal of dabigatran. Randomized trials have

not demonstrated the superiority of anticoagulants over antiplatelet

medications for strokes that appear embolic without a clear source.

However, subgroup analyses of these patients who also have moderate or severe left atrial enlargement do show benefit of OACs over

aspirin, and a randomized trial to address this strategy further is

underway.

For patients who cannot take anticoagulant medications, clopidogrel plus aspirin was compared to aspirin alone in the Atrial

Fibrillation Clopidogrel Trial with Irbesartan for Prevention of

Vascular Events (ACTIVE-A). Clopidogrel combined with aspirin

was more effective than aspirin alone in preventing vascular events,

principally stroke, but increased the risk of major bleeding (relative

risk, 1.57; p <.001). Left atrial appendage occlusion followed by

antiplatelet therapy was found to be noninferior to oral Xa inhibitors in patients at moderate to high risk of bleeding in a single trial.

If confirmed, this may be a safer strategy than management with

aspirin alone for these patients at high risk of atrial fibrillation–

related stroke.

The decision to use anticoagulation for primary prevention is

based primarily on risk factors (Table 427-3). The history of a TIA

or stroke tips the balance in favor of anticoagulation regardless of

other risk factors. Intermittent atrial fibrillation carries the same

risk of stroke as chronic atrial fibrillation, and several ambulatory

studies of seemingly “cryptogenic” stroke have found evidence

of intermittent atrial fibrillation in nearly 20% of patients monitored for a few weeks. Interrogation of implanted pacemakers also

confirms an association between subclinical atrial fibrillation and

stroke risk. Therefore, for patients with otherwise cryptogenic

embolic stroke (no evidence of any other cause for stroke), ambulatory monitoring for 3–4 weeks is a reasonable strategy to determine

the best prophylactic therapy.

Because of the high annual stroke risk in untreated rheumatic heart disease with atrial fibrillation, primary prophylaxis

against stroke has not been studied in a double-blind fashion.

These patients generally should receive long-term anticoagulation.

Dabigatran and the oral Xa inhibitors have not been studied in this

population.

Anticoagulation also reduces the risk of embolism in acute MI.

Most clinicians recommend a 3-month course of anticoagulation

when there is anterior Q-wave infarction, substantial left ventricular dysfunction, congestive heart failure, mural thrombosis, or atrial

fibrillation. OACs are recommended long term if atrial fibrillation

persists.

Stroke secondary to thromboembolism is one of the most serious

complications of prosthetic heart valve implantation. The intensity

of anticoagulation and/or antiplatelet therapy is dictated by the type

of prosthetic valve and its location. Dabigatran may be less effective

than warfarin, and the oral Xa inhibitors have not been studied in

this population.

If the embolic source cannot be eliminated, anticoagulation

should in most cases be continued indefinitely. Many neurologists

recommend combining antiplatelet agents with anticoagulants for

patients who “fail” anticoagulation (i.e., have another stroke or

TIA), but the evidence basis for this is lacking.

It is our practice to prescribe apixaban 5 mg twice daily for nonvalvular atrial fibrillation with CHA2

DS2

-VASc score of ≥2, aspirin

81 mg plus clopidogrel 75 mg daily for patients who cannot take

oral anticoagulation, and VKAs for valvular atrial fibrillation or

mechanical heart valve.

ANTICOAGULATION THERAPY AND

NONCARDIOGENIC STROKE

Data do not support the use of long-term VKAs for preventing

atherothrombotic stroke for either intracranial or extracranial cerebrovascular disease. The Warfarin-Aspirin Recurrent Stroke Study

(WARSS) found no benefit of warfarin sodium (INR 1.4–2.8) over

aspirin, 325 mg, for secondary prevention of stroke but did find

a slightly higher bleeding rate in the warfarin group; a European

study confirmed this finding. The Warfarin and Aspirin for Symptomatic Intracranial Disease (WASID) study (see below) demonstrated no benefit of warfarin (INR 2–3) over aspirin in patients

with symptomatic intracranial atherosclerosis and found a higher

rate of bleeding complications. The first of several trials testing

factor Xa medications for prevention of embolic stroke of unknown

source failed to show benefit compared to treatment with antiplatelet medications. The oral factor Xa inhibitor apixaban was found to

be noninferior to subcutaneous dalteparin for patients with cancer

3347 Ischemic Stroke CHAPTER 427

and venous thromboembolism; many oncologists are using Xa

inhibitors to prevent second stroke in patients with malignancy.

It is our practice to prescribe aspirin for secondary stroke prevention in noncardiogenic cerebral embolism except for stroke

associated with cancer (apixaban 5 mg twice daily) and the antiphospholipid syndrome (warfarin with target INR 2–3).

TREATMENT

Carotid Atherosclerosis

Carotid atherosclerosis can be removed surgically (endarterectomy)

or mitigated with endovascular stenting with or without balloon

angioplasty. Anticoagulation has not been directly compared with

antiplatelet therapy for carotid disease.

SURGICAL THERAPY

Symptomatic carotid stenosis was studied in the North American

Symptomatic Carotid Endarterectomy Trial (NASCET) and the

European Carotid Surgery Trial (ECST). Both showed a substantial

benefit for surgery in patients with stenosis of ≥70%. In NASCET,

the average cumulative ipsilateral stroke risk at 2 years was 26%

for patients treated medically and 9% for those receiving the same

medical treatment plus a carotid endarterectomy. This 17% absolute reduction in the surgical group is a 65% relative risk reduction

favoring surgery (Table 427-4). NASCET also showed a significant,

although less robust, benefit for patients with 50–70% stenosis.

ECST found harm for patients with stenosis <30% treated surgically.

A patient’s risk of stroke and possible benefit from surgery are

related to the presence of retinal versus hemispheric symptoms,

degree of arterial stenosis, extent of associated medical conditions

(of note, NASCET and ECST excluded “high-risk” patients with significant cardiac, pulmonary, or renal disease), institutional surgical

morbidity and mortality, timing of surgery relative to symptoms,

and other factors. A recent meta-analysis of the NASCET and ECST

trials demonstrated that endarterectomy is most beneficial when

performed within 2 weeks of symptom onset. In addition, benefit is

more pronounced in patients >75 years, and men appear to benefit

more than women.

In summary, a patient with recent symptomatic hemispheric

ischemia, high-grade stenosis in the appropriate internal carotid

artery, and an institutional perioperative morbidity and mortality

rate of ≤6% generally should undergo carotid endarterectomy. If

the perioperative stroke rate is >6% for any particular surgeon,

however, the benefits of carotid endarterectomy are questionable.

The indications for surgical treatment of asymptomatic carotid

disease have been clarified by the results of the Asymptomatic

Carotid Atherosclerosis Study (ACAS) and the Asymptomatic

Carotid Surgery Trial (ACST). ACAS randomized asymptomatic

patients with ≥60% stenosis to medical treatment with aspirin

or the same medical treatment plus carotid endarterectomy. The

surgical group had a risk over 5 years for ipsilateral stroke (and any

perioperative stroke or death) of 5.1%, compared to a risk in the

medical group of 11%. Although this demonstrates a 53% relative

risk reduction, the absolute risk reduction is only 5.9% over 5 years,

or 1.2% annually (Table 427-4). Nearly one-half of the strokes in

the surgery group were caused by preoperative angiograms. ACST

randomized asymptomatic patients with >60% carotid stenosis to

endarterectomy or medical therapy. The 5-year risk of stroke in the

surgical group (including perioperative stroke or death) was 6.4%,

compared to 11.8% in the medically treated group (46% relative risk

reduction and 5.4% absolute risk reduction).

In both ACAS and ACST, the perioperative complication rate

was higher in women, perhaps negating any benefit in the reduction

of stroke risk within 5 years. It is possible that with longer follow-up,

a clear benefit in women will emerge. At present, carotid endarterectomy in asymptomatic women remains particularly controversial.

In summary, the natural history of asymptomatic stenosis is an

~2% per year stroke rate, whereas symptomatic patients experience

a 13% per year risk of stroke. Whether to recommend carotid

revascularization for an asymptomatic patient is somewhat controversial and depends on many factors, including patient preference,

degree of stenosis, age, gender, and comorbidities. Medical therapy

for reduction of atherosclerosis risk factors, including cholesterollowering agents and antiplatelet medications, is generally recommended for patients with asymptomatic carotid stenosis. As with

atrial fibrillation, it is imperative to counsel the patient about TIAs

so that therapy can be revised if symptoms develop.

ENDOVASCULAR THERAPY

Balloon angioplasty coupled with stenting is being used with

increasing frequency to open stenotic carotid arteries and maintain

their patency. These techniques can treat carotid stenosis not only

at the bifurcation but also near the skull base and in the intracranial

segments. The Stenting and Angioplasty with Protection in Patients

at High Risk for Endarterectomy (SAPPHIRE) trial randomized

high-risk patients (defined as patients with clinically significant

coronary or pulmonary disease, contralateral carotid occlusion,

restenosis after endarterectomy, contralateral laryngeal-nerve palsy,

prior radical neck surgery or radiation, or age >80) with symptomatic carotid stenosis >50% or asymptomatic stenosis >80% to

either stenting combined with a distal emboli-protection device or

endarterectomy. The risk of death, stroke, or MI within 30 days and

ipsilateral stroke or death within 1 year was 12.2% in the stenting

group and 20.1% in the endarterectomy group (p = .055), suggesting that stenting is at the very least comparable to endarterectomy

as a treatment option for this patient group at high risk of surgery.

However, the outcomes with both interventions may not have been

better than leaving the carotid stenoses untreated, particularly for

the asymptomatic patients, and much of the benefit seen in the

stenting group was due to a reduction in periprocedure MI. Two

randomized trials comparing stents to endarterectomy in lower-risk patients have been published. The Carotid Revascularization

Endarterectomy versus Stenting Trial (CREST) enrolled patients

with either asymptomatic or symptomatic stenosis. The 30-day

risk of stroke was 4.1% in the stent group and 2.3% in the surgical

group, but the 30-day risk of MI was 1.1% in the stent group and

2.3% in the surgery group, suggesting relative equivalence of risk

between the procedures. At median follow-up of 2.5 years, the

combined endpoint of stroke, MI, and death was the same (7.2%

stent vs 6.8% surgery) and remained so at 10-year follow-up. The

rate of restenosis at 2 years was also similar in both groups. The

International Carotid Stenting Study (ICSS) randomized symptomatic patients to stents versus endarterectomy and found a different

result: at 120 days, the incidence of stroke, MI, or death was 8.5%

in the stenting group versus 5.2% in the endarterectomy group

(p = .006). At median follow-up of 5 years, these differences were

no longer significant except a small increase in nondisabling stroke

in the stenting group but no change in the average disability. In

meta-analysis, carotid endarterectomy (CEA) is less morbid in

older patients (aged ≥70) than is stenting. Investigation is ongoing

in asymptomatic patients to compare medical therapy to stenting

and CEA. This will likely answer how well medical patients do

with more modern medical therapy (statins, close blood pressure

control, and lifestyle modification).

BYPASS SURGERY

Extracranial-to-intracranial (EC-IC) bypass surgery has been

proven ineffective for atherosclerotic stenoses that are inaccessible

to conventional CEA. In patients with recent stroke, an associated

carotid occlusion, and evidence of inadequate perfusion of the brain

as measured with positron emission tomography, no benefit from

EC-IC bypass was found in a trial stopped for futility.

PATENT FORAMEN OVALE (PFO)

In patients with PFO and/or atrial septal aneurysm with an embolic

stroke and no other cause identified, three randomized trials

using various endovascular closure devices individually and in

meta-analysis report a significant (1% per year) reduction in second

3348 PART 13 Neurologic Disorders

stroke compared to antiplatelet agents. If the neurological opinion

is that no other source of stroke is identified and consultation with a

cardiologist knowledgeable about PFO closure supports intervention,

we recommend endovascular PFO closure.

INTRACRANIAL ATHEROSCLEROSIS

The WASID trial randomized patients with symptomatic stenosis

(50–99%) of a major intracranial vessel to either high-dose aspirin

(1300 mg/d) or warfarin (target INR, 2.0–3.0), with a combined

primary endpoint of ischemic stroke, brain hemorrhage, or death

from vascular cause other than stroke. The trial was terminated

early because of an increased risk of adverse events related to

warfarin anticoagulation. With a mean follow-up of 1.8 years, the

primary endpoint was seen in 22.1% of patients in the aspirin group

and 21.8% of the warfarin group. Death from any cause was seen in

4.3% of the aspirin group and 9.7% of the warfarin group; 3.2% of

patients on aspirin experienced major hemorrhage, compared to

8.3% of patients taking warfarin.

Intracranial stenting of intracranial atherosclerosis was found to

be dramatically harmful compared to aspirin in the Stenting and

Aggressive Medical Management for Preventing Recurrent Stroke

in Intracranial Stenosis (SAMMPRIS) trial. This trial enrolled newly

symptomatic TIA or minor stroke patients with associated 70–99%

intracranial stenosis to primary stenting with a self-expanding stent

or to medical management. Both groups received clopidogrel, aspirin, statin, and aggressive control of blood pressure. The endpoint

of stroke or death occurred in 14.7% of the stented group and 5.8%

of the medically treated groups (p = .002). This low rate of second

stroke was significantly lower than in the WASID trial and suggests

that aggressive medical management had a marked influence on

secondary stroke risk. A concomitant study of balloon-expandable

stenting was halted early at 125 patients because of the negative

SAMMPRIS results and due to harm. Therefore, routine use of

intracranial stenting is harmful, and medical therapy is superior for

intracranial atherosclerosis.

Dural Sinus Thrombosis Limited evidence exists to support

short-term use of anticoagulants, regardless of the presence of

intracranial hemorrhage, for venous infarction following sinus

thrombosis. The long-term outcome for most patients, even those

with intracerebral hemorrhage, is excellent.

■ FURTHER READING

Goyal M et al: Endovascular thrombectomy after large-vessel

ischaemic stroke: A meta-analysis of individual patient data from

five randomised trials. Lancet 387:1723, 2016.

Grotta JC et al: Prospective, multicenter, controlled trial of mobile

stroke units. N Engl J Med 385:971, 2021.

January CT et al: 2019 AHA/ACC/HRS focused update of the 2014

AHA/ACC/HRS guideline for the management of patients with atrial

fibrillation: A report of the American College of Cardiology/American

Heart Association Task Force on Clinical Practice Guidelines and the

Heart Rhythm Society. J Am Coll Cardiol 74:104, 2019.

Larsson SC et al: Prognosis of carotid dissecting aneurysms: Results

from CADISS and a systematic review. Neurology 88:646, 2017.

Osmancik P et al: Left atrial appendage closure versus direct oral

anticoagulants in high-risk patients with atrial fibrillation. J Am Coll

Cardiol 75:3122, 2020.

Powers WJ et al: Guidelines for the early management of patients with

acute ischemic stroke: 2019 update to the 2018 guidelines for the early

management of acute ischemic stroke: A guideline for healthcare

professionals from the American Heart Association/American Stroke

Association. Stroke 50:e344, 2019.

Saver JL et al: Time to treatment with endovascular thrombectomy and outcomes from ischemic stroke: A meta-analysis. JAMA

316:1279, 2016.

Sprint Research Group et al: A randomized trial of intensive versus

standard blood-pressure control. N Engl J Med 373:2103, 2015.

Torbey MT et al: Evidence-based guidelines for the management of

large hemispheric infarction: A statement for health care professionals

from the Neurocritical Care Society and the German Society for Neuro-intensive Care and Emergency Medicine. Neurocrit Care 22:146,

2015.

Intracranial hemorrhage is a form of stroke (see Chap. 426). Compared to ischemic stroke, patients with intracranial hemorrhage are

more likely to present with headache; however, brain imaging is

required to distinguish these entities. CT imaging of the head is highly

sensitive and specific for intracranial hemorrhage and determines the

location(s) of bleeding. Hemorrhages are classified by their location

and the underlying vascular pathology. Hemorrhage directly into the

brain parenchyma, also known as intracerebral hemorrhage (ICH), and

arteriovenous malformations (AVMs) of the brain will be considered

here. Other categories of hemorrhage include bleeding into subdural

and epidural spaces, usually caused by trauma (Chap 443), and subarachnoid hemorrhage due to trauma or the rupture of an intracranial

aneurysm (Chap. 429).

■ DIAGNOSIS

Intracranial hemorrhage is often identified on noncontrast CT imaging of the brain during the acute evaluation of stroke. Because CT is

more widely available and may be logistically easier to perform than

MRI, CT imaging is generally the preferred method for acute stroke

evaluation (Fig. 428-1). The location of the hemorrhage narrows the

differential diagnosis to a few entities. Table 428-1 lists the causes and

anatomic spaces involved in hemorrhages.

■ EMERGENCY MANAGEMENT

Close attention should be paid to airway management because a reduction in the level of consciousness is common and often progressive.

The initial blood pressure should be maintained until the results of the

428 Intracranial Hemorrhage

Wade S. Smith, J. Claude Hemphill, III,

S. Claiborne Johnston

FIGURE 428-1 Hypertensive hemorrhage. Transaxial noncontrast computed

tomography scan through the region of the basal ganglia reveals a hematoma

involving the left putamen in a patient with rapidly progressive onset of right

hemiparesis.

3349 Intracranial Hemorrhage CHAPTER 428

presentation or who are deeply comatose with possible elevated intracranial pressure (ICP). In patients who have ICP monitors in place,

current recommendations are that maintaining the cerebral perfusion

pressure (mean arterial pressure [MAP] minus ICP) at 50–70 mmHg

is reasonable, depending on the individual patient’s cerebral autoregulation status (Chap. 307). Blood pressure should be lowered with

nonvasodilating IV drugs such as nicardipine, labetalol, or esmolol.

Patients with cerebellar hemorrhages with depressed mental status or

radiographic evidence of hydrocephalus should undergo urgent neurosurgical evaluation; these patients require close monitoring because

they can deteriorate rapidly. Based on the clinical examination and CT

findings, further imaging studies may be necessary, including MRI or

conventional x-ray angiography. Stuporous or comatose patients with

clinical and imaging signs of herniation are generally treated presumptively for elevated ICP with tracheal intubation and sedation, administration of osmotic diuretics such as mannitol or hypertonic saline, and

elevation of the head of the bed while surgical consultation is obtained

(Chap. 307). Reversal of coagulopathy and consideration of surgical

evacuation of the hematoma (detailed below) are two other principal

aspects of initial emergency management.

■ INTRACEREBRAL HEMORRHAGE

ICH accounts for ~10% of all strokes, and ~35–45% of patients die

within the first month. Incidence rates are particularly high in Asians

and blacks. Hypertension, coagulopathy, sympathomimetic drugs

(cocaine, methamphetamine), and cerebral amyloid angiopathy (CAA)

cause most of these hemorrhages. Advanced age, heavy alcohol, and

low-dose aspirin use in those without symptomatic cardiovascular

disease increase the risk, and cocaine or methamphetamine use is one

of the most important causes in the young.

Hypertensive ICH • PATHOPHYSIOLOGY Hypertensive ICH

usually results from spontaneous rupture of a small penetrating artery

deep in the brain. The most common sites are the basal ganglia (especially the putamen), thalamus, cerebellum, and pons. The small arteries in these areas seem most prone to hypertension-induced vascular

injury. When hemorrhages occur in other brain areas or in nonhypertensive patients, greater consideration should be given to other causes

such as hemorrhagic disorders, neoplasms, vascular malformations,

vasculitis, and CAA. The hemorrhage may be small, or a large clot

may form and compress adjacent tissue, causing herniation and death.

Blood may also dissect into the ventricular space, which substantially

increases morbidity and may cause hydrocephalus.

Most hypertensive ICHs initially develop over 30–90 min, whereas

those associated with anticoagulant therapy may evolve for as long

as 24–48 h. It is now recognized that about a third of patients even

with no coagulopathy may have significant hematoma expansion

with the first day. Within 48 h, macrophages begin to phagocytize the

hemorrhage at its outer surface. After 1–6 months, the hemorrhage

is generally resolved to a slitlike cavity lined with a glial scar and

hemosiderin-laden macrophages.

CLINICAL MANIFESTATIONS ICH generally presents as the abrupt

onset of a focal neurologic deficit. Seizures are uncommon. Although

clinical symptoms may be maximal at onset, more commonly, the focal

deficit worsens over 30–90 min and is associated with a diminishing

level of consciousness and signs of increased ICP such as headache

and vomiting.

The putamen is the most common site for hypertensive hemorrhage,

and the adjacent internal capsule is usually damaged (Fig. 428-1).

Contralateral hemiparesis is therefore the sentinel sign. When mild,

the face sags on one side over 5–30 min, speech becomes slurred, the

arm and leg gradually weaken, and the eyes deviate away from the side

of the hemiparesis. The paralysis may worsen until the affected limbs

become flaccid or extend rigidly. When hemorrhages are large, drowsiness gives way to stupor as signs of upper brainstem compression

appear. Coma ensues, accompanied by deep, irregular, or intermittent

respiration, a dilated and fixed ipsilateral pupil, and decerebrate rigidity. In milder cases, edema in adjacent brain tissue may cause progressive deterioration over 12–72 h.

TABLE 428-1 Causes of Intracranial Hemorrhage

CAUSE LOCATION COMMENTS

Head trauma Intraparenchymal: frontal

lobes, anterior temporal

lobes; subarachnoid;

extra-axial (subdural,

epidural)

Coup and contrecoup injury

during brain deceleration

Hypertensive

hemorrhage

Putamen, globus pallidus,

thalamus, cerebellar

hemisphere, pons

Chronic hypertension

produces hemorrhage from

small (~30–100 μm) vessels in

these regions

Transformation

of prior ischemic

infarction

Basal ganglion,

subcortical regions, lobar

Occurs in 1–6% of ischemic

strokes with predilection for

large hemispheric infarctions

Metastatic brain

tumor

Lobar Lung, choriocarcinoma,

melanoma, renal cell

carcinoma, thyroid, atrial

myxoma

Coagulopathy Any Risk for ongoing hematoma

expansion

Drug Any, lobar, subarachnoid Cocaine, amphetamine

Arteriovenous

malformation

Lobar, intraventricular,

subarachnoid

Risk is ~2–3% per year

for bleeding if previously

unruptured

Aneurysm Subarachnoid,

intraparenchymal, rarely

subdural

Mycotic and nonmycotic

forms of aneurysms

Amyloid angiopathy Lobar Degenerative disease

of intracranial vessels;

associated with dementia,

rare in patients <60 years

Cavernous angioma Intraparenchymal Multiple cavernous angiomas

linked to mutations in KRIT1,

CCM2, and PDCD10 genes

Dural arteriovenous

fistula

Lobar, subarachnoid Produces bleeding by venous

hypertension

Dural sinus

thrombosis

Along sagittal sinus,

posterior temporal/

inferior parietal

Sagittal sinus thrombosis

can cause hemispheric

parasagittal hemorrhage

with edema; vein of Labbé

occlusion from transverse

sinus occlusion produces

posterior temporal/inferior

parietal hemorrhage

Capillary

telangiectasias

Usually brainstem Rare cause of hemorrhage

CT scan are reviewed and demonstrate ICH. In theory, a higher blood

pressure should promote hematoma expansion, but it remains unclear

if lowering of blood pressure reduces hematoma growth. Recent clinical trials have shown that systolic blood pressure (SBP) can be safely

lowered acutely and rapidly to <140 mmHg in patients with spontaneous ICH whose initial SBP was 150–220 mmHg. The INTERACT2

trial was a large phase 3 clinical trial to address the effect of acute

blood pressure lowering on ICH functional outcome. INTERACT2

randomized patients with spontaneous ICH within 6 h of onset and a

baseline SBP of 150–220 mmHg to two different SBP targets (<140 and

<180 mmHg). In those with the target SBP <140 mmHg, 52% had an

outcome of death or major disability at 90 days compared with 55.6% of

those with a target SBP <180 mmHg (p = .06). There was a significant

shift to improved outcomes in the lower blood pressure arm, whereas

both groups had a similar mortality. ATACH2 was a similarly designed

clinical trial that assessed the same blood pressure targets but demonstrated no difference in outcome between groups. Current U.S. and

European guidelines emphasize that blood pressure lowering to a target

SBP is likely safe and possibly beneficial. However, these guidelines

were completed prior to publication of the ATACH2 results; thus, the

specific optimal target remains a point of debate. It is unclear whether

these clinical trial results apply to patients who have higher SBP on

 

3338 PART 13 Neurologic Disorders

Endovascular mechanical thrombectomy has been studied as

an alternative or adjunctive treatment of acute stroke in patients

who are ineligible for, or have contraindications to, thrombolytics

or in those who failed to achieve vascular recanalization with IV

thrombolytics (see Fig. 426-12). In 2015, the results of six randomized trials were published, all demonstrating that endovascular

therapy improved clinical outcomes for internal carotid and MCA

occlusions proven by CT angiography (CTA), under 6 h from stroke

onset, with or without pretreatment with IV tissue plasminogen

activator (tPA). One study concluded that patients were home

nearly 2 months earlier if they received endovascular therapy. A

combined meta-analysis of all patients in these trials confirmed

a large benefit with endovascular therapy (odds ratio [OR], 2.49;

95% confidence interval [CI], 1.76–3.53; p <.001). The percentage

of patients who achieved modified Rankin scores of 0–2 (normal

or symptomatic but independent) was 46% in the endovascular

group and 26.5% in the medical arm. A more recent meta-analysis

reveals a mortality benefit as well with thrombectomy. As with IV

rtPA treatment, clinical outcome is dependent on time to effective

therapy. The odds of a good outcome exceed 3 if groin puncture

occurs within 2 h of symptom onset but is only 2 if 8 h elapse. Over

80% of patients who had vessel opening within 1 h of arrival to the

emergency department had a good outcome, whereas only onethird had a good outcome if 6 h elapsed.

The outcomes from endovascular therapy are likely improved

with IV rtPA treatment prior to thrombectomy if the patient is

eligible for rtPA and it is safe to administer. Recent data support

replacing IV rtPA with IV tenecteplase because its simple bolus

administration makes transporting the patient to an endovascular

center less cumbersome.

Extending the time window beyond 6 h appears to be effective

if the patient has specific imaging findings demonstrating good

vascular collaterals (CT perfusion or magnetic resonance [MR] perfusion techniques, see Chap. 426) and can be treated within 24 h.

The Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention with Trevo (DAWN)

trial reported good outcomes more frequently with endovascular

therapy than with medical care alone (47 vs 13%, p <.0001). The

Endovascular Therapy Following Imaging Evaluation for Ischemic

Stroke 3 (DEFUSE-3) trial confirmed these results (45 vs 17%,

p <.001) if treated up to 16 h from stroke onset. Nonrandomized

data of thrombectomy for basilar occlusion have found this treatment to be safe up to 24 h from symptom onset and associated with

lower 3-month Rankin scores.

Now that endovascular stroke therapy is proven to be effective,

the creation of comprehensive stroke centers designed to rapidly

identify and treat patients with large-vessel cerebral ischemia is a

major focus internationally. Creating geographic systems of care

whereby stroke patients are first evaluated at primary stroke centers

(which can administer IV rtPA or tenecteplase) then transferred to

comprehensive centers if needed, or directly triaged to comprehensive centers based on field assessment, appears to be an effective

strategy to improve outcomes.

ANTITHROMBOTIC TREATMENT

Platelet Inhibition Aspirin is the only antiplatelet agent that has

been proven to be effective for the acute treatment of ischemic

stroke; there are several antiplatelet agents proven for the secondary

prevention of stroke (see below). Two large trials, the International

Stroke Trial (IST) and the Chinese Acute Stroke Trial (CAST),

found that the use of aspirin within 48 h of stroke onset reduced

both stroke recurrence risk and mortality minimally. Among

19,435 patients in IST, those allocated to aspirin, 300 mg/d, had

slightly fewer deaths within 14 days (9.0 vs 9.4%), significantly

fewer recurrent ischemic strokes (2.8 vs 3.9%), no excess of hemorrhagic strokes (0.9 vs 0.8%), and a trend toward a reduction in

death or dependence at 6 months (61.2 vs 63.5%). In CAST, 21,106

patients with ischemic stroke received 160 mg/d of aspirin or a

placebo for up to 4 weeks. There were very small reductions in the

aspirin group in early mortality (3.3 vs 3.9%), recurrent ischemic

strokes (1.6 vs 2.1%), and dependency at discharge or death (30.5

vs 31.6%). These trials demonstrate that the use of aspirin in the

treatment of AIS is safe and produces a small net benefit. For every

1000 acute strokes treated with aspirin, ~9 deaths or nonfatal stroke

recurrences will be prevented in the first few weeks and ~13 fewer

patients will be dead or dependent at 6 months. Combining aspirin

with clopidogrel or with ticagrelor following minor stroke or TIA is

effective at preventing second stroke (see below).

Anticoagulation Numerous clinical trials have failed to demonstrate any benefit of routine anticoagulation in the primary treatment of atherothrombotic cerebral ischemia and have also shown

an increase in the risk of brain and systemic hemorrhage. Therefore,

the routine use of heparin or other anticoagulants for patients

with atherothrombotic stroke is not warranted. Heparin and oral

anticoagulation are likely no more effective than aspirin for stroke

associated with arterial dissection. However, there may be benefit of

anticoagulation for halting progression of dural sinus thrombosis.

NEUROPROTECTION

Neuroprotection is the concept of providing a treatment that prolongs the brain’s tolerance to ischemia. Drugs that block the excitatory amino acid pathways have been shown to protect neurons and

glia in animals, but despite multiple human trials, they have not yet

been proven to be beneficial. Hypothermia is a powerful neuroprotective treatment in patients with cardiac arrest (Chap. 307) and is

neuroprotective in animal models of stroke, but it has not been adequately studied in patients with ischemic stroke and is associated

with an increase in pneumonia rates that could adversely impact

stroke outcomes. Hypothermia combined with hemicraniectomy is

no more effective than hemicraniectomy with euthermia.

STROKE CENTERS AND REHABILITATION

Patient care in stroke units followed by rehabilitation services

improves neurologic outcomes and reduces mortality. Use of clinical

pathways and staff dedicated to the stroke patient can improve care.

This includes use of standardized stroke order sets. Stroke teams

TABLE 427-1 Administration of Intravenous Recombinant Tissue

Plasminogen Activator (rtPA) for Acute Ischemic Stroke (AIS)a

INDICATION CONTRAINDICATION

Clinical diagnosis of stroke

Onset of symptoms to time of drug

administration ≤4.5 hb

CT scan showing no hemorrhage or

edema of >1/3 of the MCA territory

Age ≥18 years

Sustained BP >185/110 mmHg despite

treatment

Bleeding diathesis

Recent head injury or intracerebral

hemorrhage

Major surgery in preceding 14 days

Gastrointestinal bleeding in preceding

21 days

Recent myocardial infarction

Administration of rtPA

IV access with two peripheral IV lines (avoid arterial or central line placement)

Review eligibility for rtPA

Administer 0.9 mg/kg IV (maximum 90 mg) IV as 10% of total dose by bolus,

followed by remainder of total dose over 1 hc

Frequent cuff BP monitoring

No other antithrombotic treatment for 24 h

For decline in neurologic status or uncontrolled BP, stop infusion, give

cryoprecipitate, and reimage brain emergently

Avoid urethral catheterization for ≥2 h

a

See Activase (tissue plasminogen activator) package insert for complete list of

contraindications and dosing. b

Depending on the country, IV rtPA may be approved

for up to 4.5 h with additional restrictions. c

A dose of 0.6 mg/kg is commonly used in

Asia (Japan and China) based on randomized data indicating less hemorrhage and

similar efficacy using this lower dose.

Abbreviations: BP, blood pressure; CT, computed tomography; MCA, middle cerebral

artery.

3339 Ischemic Stroke CHAPTER 427

that provide emergency 24-h evaluation of acute stroke patients for

acute medical management and consideration of thrombolysis or

endovascular treatments are essential components of primary and

comprehensive stroke centers, respectively.

Proper rehabilitation of the stroke patient includes early physical,

occupational, and speech therapy. It is directed toward educating

the patient and family about the patient’s neurologic deficit, preventing the complications of immobility (e.g., pneumonia, DVT

and pulmonary embolism, pressure sores of the skin, and muscle

contractures), and providing encouragement and instruction in

overcoming the deficit. Use of pneumatic compression stockings is

of proven benefit in reducing risk of DVT and is a safe alternative

to heparin. The goal of rehabilitation is to return the patient home

and to maximize recovery by providing a safe, progressive regimen

suited to the individual patient. Additionally, the use of constrained

movement therapy (immobilizing the unaffected side) has been

shown to improve hemiparesis following stroke, even years after

the stroke, suggesting that physical therapy can recruit unused

neural pathways. Controversy exists regarding whether selective

serotonin uptake inhibitors improve motor recovery but they may

be helpful in preventing poststroke depression. Newer robotic therapies appear promising as well. The human nervous system is more

adaptable than previously thought, and developing physical and

pharmacologic strategies to enhance long-term neural recovery is

an active area of research.

■ ETIOLOGY OF ISCHEMIC STROKE

(Fig. 427-3 and Table 427-2) Although the initial management of

AIS often does not depend on the etiology, establishing a cause is

essential to reduce the risk of recurrence. Focus should be on atrial

fibrillation and carotid atherosclerosis, because these etiologies have

proven secondary prevention strategies. The clinical presentation and

examination findings often establish the cause of stroke or narrow the

possibilities to a few. Judicious use of laboratory testing and imaging

studies completes the initial evaluation. Nevertheless, nearly 30% of

strokes remain unexplained despite extensive evaluation.

Clinical examination should focus on the peripheral and cervical

vascular system (measuring blood pressure), the heart (dysrhythmia,

murmurs), extremities (peripheral emboli), and retina (effects of

hypertension and cholesterol emboli [Hollenhorst plaques]). A complete neurologic examination is performed to localize the anatomic

site of stroke (Chap. 426). An imaging study of the brain is nearly

always indicated and is required for patients being considered for

thrombolysis; it may be combined with CT- or MRI-based angiography to visualize the vasculature of the neck and intracranial vessels

(see “Imaging Studies,” Chap. 426). A chest x-ray, electrocardiogram

(ECG), urinalysis, complete blood count, erythrocyte sedimentation

rate (ESR), serum electrolytes, blood urea nitrogen (BUN), creatinine, blood glucose, serum lipid profile, prothrombin time (PT), and

partial thromboplastin time (PTT) are often useful and should be

considered in all patients. An ECG, and subsequent cardiac telemetry,

may demonstrate arrhythmias or reveal evidence of recent myocardial

infarction (MI). Of all these studies, only brain imaging is necessary

prior to IV rtPA; the results of other studies should not delay the rapid

administration of IV rtPA if the patient is eligible.

Cardioembolic Stroke Cardioembolism is responsible for ~20%

of all ischemic strokes. Stroke caused by heart disease is primarily

due to embolism of thrombotic material forming on the atrial or

ventricular wall or the left heart valves. These thrombi then detach

and embolize into the arterial circulation. The thrombus may fragment or lyse quickly, producing only a TIA. Alternatively, the arterial

occlusion may last longer, producing stroke. Embolic strokes tend to

occur suddenly with maximum neurologic deficit present at onset.

With reperfusion following more prolonged ischemia, petechial hemorrhages can occur within the ischemic territory. These are usually

of no clinical significance and should be distinguished from frank

intracranial hemorrhage into a region of ischemic stroke where the

mass effect from the hemorrhage can cause a significant decline in

neurologic function.

Emboli from the heart most often lodge in the intracranial internal

carotid artery, the MCA, the posterior cerebral artery (PCA), or one

of their branches; infrequently, the anterior cerebral artery (ACA) is

Left ventricular

thrombi

Valve disease

Atrial fibrillation

Flowreducing

carotid

stenosis

External

carotid

Common

carotid

Internal

carotid

Cardiogenic

emboli

Carotid

plaque with

arteriogenic

emboli

Intracranial

atherosclerosis

Penetrating

artery disease

A B C

FIGURE 427-3 Pathophysiology of ischemic stroke. A. Diagram illustrating the three major mechanisms that underlie ischemic stroke: (1) occlusion of an intracranial vessel

by an embolus (e.g., cardiogenic sources such as atrial fibrillation or artery-to-artery emboli from carotid atherosclerotic plaque), often affecting the large intracranial

vessels; (2) in situ thrombosis of an intracranial vessel, typically affecting the small penetrating arteries that arise from the major intracranial arteries; (3) hypoperfusion

caused by flow-limiting stenosis of a major extracranial (e.g., internal carotid) or intracranial vessel, often producing “watershed” ischemia. B. and C. Diagram and

reformatted computed tomography angiogram of the common, internal, and external carotid arteries. High-grade stenosis of the internal carotid artery, which may be

associated with either cerebral emboli or flow-limiting ischemia, was identified in this patient.

3340 PART 13 Neurologic Disorders

involved. Emboli large enough to occlude the stem of the MCA (3–4

mm) or internal carotid terminus lead to large infarcts that involve

both deep gray and white matter and some portions of the cortical surface and its underlying white matter. A smaller embolus may occlude

a small cortical or penetrating arterial branch. The location and size

of an infarct within a vascular territory depend on the extent of the

collateral circulation.

The most significant cause of cardioembolic stroke in most of the

world is nonrheumatic (often called nonvalvular) atrial fibrillation. MI,

prosthetic valves, rheumatic heart disease, and ischemic cardiomyopathy are other considerations (Table 427-2). Cardiac disorders causing

brain embolism are discussed in the chapters on heart diseases, but a

few pertinent aspects are highlighted here.

Nonrheumatic atrial fibrillation is the most common cause of cerebral embolism overall. The presumed stroke mechanism is thrombus

formation in the fibrillating atrium or atrial appendage, with subsequent embolization. Patients with atrial fibrillation have an average

annual risk of stroke of ~5%. The risk of stroke can be estimated

by calculating the CHA2

DS2

-VASc score (Table 427-3). Left atrial

enlargement is an additional risk factor for formation of atrial thrombi.

Rheumatic heart disease usually causes ischemic stroke when there

is prominent mitral stenosis or atrial fibrillation. Recent MI may be

a source of emboli, especially when transmural and involving the

anteroapical ventricular wall, and prophylactic anticoagulation following MI with left ventricular thrombus has been shown to reduce

ischemic stroke risk. Mitral valve prolapse is not usually a source of

emboli unless the prolapse is severe.

Paradoxical embolization occurs when venous thrombi migrate to

the arterial circulation, usually via a patent foramen ovale (PFO) or

atrial septal defect. Bubble-contrast echocardiography (IV injection

of agitated saline coupled with either transthoracic or transesophageal echocardiography) can demonstrate a right-to-left cardiac shunt,

revealing the conduit for paradoxical embolization. Alternatively, a

right-to-left shunt is implied if immediately following IV injection of

agitated saline, the ultrasound signature of bubbles is observed during

transcranial Doppler insonation of the MCA; pulmonary arteriovenous malformations should be considered if this test is positive yet

an echocardiogram fails to reveal an intracardiac shunt. Both techniques are highly sensitive for detection of right-to-left shunts. Besides

venous clot, fat and tumor emboli, bacterial endocarditis, IV air, and

amniotic fluid emboli at childbirth may occasionally be responsible

for paradoxical embolization. The importance of a PFO as a cause

of stroke is debated, particularly because they are present in ~15% of

the general population. The presence of a venous source of embolus,

most commonly a deep-venous thrombus, may provide confirmation

of the importance of a PFO with an accompanying right-to-left shunt

in a particular case. Meta-analysis of three recent randomized trials

reported a hazard ratio of 0.41 for recurrent stroke (about a 1% per year

absolute reduction) using percutaneous occlusion devices in patients

with no other explanation for their stroke. Guidelines now endorse

PFO closure with percutaneous devices after consultation with a neurologist and a cardiologist. This is the practice followed by the authors.

Bacterial endocarditis can be a source of valvular vegetations that

give rise to septic emboli. The appearance of multifocal symptoms

and signs in a patient with stroke makes bacterial endocarditis more

likely. Infarcts of microscopic size occur, and large septic infarcts may

evolve into brain abscesses or cause hemorrhage into the infarct, which

generally precludes use of anticoagulation or thrombolytics. Mycotic

aneurysms caused by septic emboli may also present as subarachnoid

hemorrhage (SAH) or intracerebral hemorrhage.

Artery-to-Artery Embolic Stroke Thrombus formation on atherosclerotic plaques may embolize to intracranial arteries producing

an artery-to-artery embolic stroke. Less commonly, a diseased vessel

may acutely thrombose. Unlike the myocardial vessels, artery-to-artery

embolism, rather than local thrombosis, appears to be the dominant

vascular mechanism causing large-vessel brain ischemia. Any diseased

vessel may be an embolic source, including the aortic arch, common

carotid, internal carotid, vertebral, and basilar arteries.

CAROTID ATHEROSCLEROSIS Atherosclerosis within the carotid

artery occurs most frequently within the common carotid bifurcation

and proximal internal carotid artery; the carotid siphon (portion

within the cavernous sinus) is also vulnerable to atherosclerosis. Male

gender, older age, smoking, hypertension, diabetes, and hypercholesterolemia are risk factors for carotid disease, as they are for stroke in

general (Table 427-4). Carotid atherosclerosis produces an estimated

10% of ischemic stroke. For further discussion of the pathogenesis of

atherosclerosis, see Chap. 237.

Carotid disease can be classified by whether the stenosis is symptomatic or asymptomatic and by the degree of stenosis (percent narrowing of the narrowest segment compared to a nondiseased segment).

Symptomatic carotid disease implies that the patient has experienced

TABLE 427-2 Causes of Ischemic Stroke

COMMON CAUSES UNCOMMON CAUSES

Thrombosis

Lacunar stroke (small vessel)

Large-vessel thrombosis

Dehydration

Embolic occlusion

Artery-to-artery

 Carotid bifurcation

 Aortic arch

 Arterial dissection

Cardioembolic

 Atrial fibrillation

 Mural thrombus

 Myocardial infarction

 Dilated cardiomyopathy

 Valvular lesions

 Mitral stenosis

 Mechanical valve

 Bacterial endocarditis

Paradoxical embolus

 Atrial septal defect

 Patent foramen ovale

Atrial septal aneurysm

Spontaneous echo contrast

 Stimulant drugs: cocaine,

amphetamine

Hypercoagulable disorders

Protein C deficiencya

Protein S deficiencya

Antithrombin III deficiencya

Antiphospholipid syndrome

Factor V Leiden mutationa

Prothrombin G20210 mutationa

Systemic malignancy

Sickle cell anemia

β Thalassemia

Polycythemia vera

Systemic lupus erythematosus

Homocysteinemia

Thrombotic thrombocytopenic

purpura

Disseminated intravascular

coagulation

Dysproteinemiasa

Nephrotic syndromea

Inflammatory bowel diseasea

Oral contraceptives

COVID-19 infection

Venous sinus thrombosisb

Fibromuscular dysplasia

Vasculitis

 Systemic vasculitis (PAN,

 granulomatosis with polyangiitis

[Wegener’s], Takayasu’s, giant cell

arteritis)

Primary CNS vasculitis

Meningitis (syphilis, tuberculosis,

fungal, bacterial, zoster)

Noninflammatory vasculopathy

Reversible vasoconstriction

syndrome

Fabry’s disease

Angiocentric lymphoma

Cardiogenic

Mitral valve calcification

Atrial myxoma

Intracardiac tumor

Marantic endocarditis

Libman-Sacks endocarditis

Subarachnoid hemorrhage vasospasm

Moyamoya disease

Eclampsia

a

Chiefly cause venous sinus thrombosis. b

May be associated with any

hypercoagulable disorder.

Abbreviations: CNS, central nervous system; PAN, polyarteritis nodosa.

3341 Ischemic Stroke CHAPTER 427

TABLE 427-3 Recommendations on Chronic Use of Antithrombotics

for Various Cardiac Conditions

CONDITION RECOMMENDATION

Nonvalvular atrial fibrillation Calculate CHA2

DS2

-VASc scorea

• CHA2

DS2

-VASc score of 0 Aspirin or no antithrombotic

• CHA2

DS2

-VASc score of 1 Aspirin or OAC

• CHA2

DS2

-VASc score of ≥2 OAC

Rheumatic mitral valve disease

• With atrial fibrillation, previous

embolization, or atrial appendage thrombus,

or left atrial diameter >55 mm

OAC

• Embolization or appendage clot despite OAC OAC plus aspirin

Mitral valve prolapse

• Asymptomatic No therapy

• With otherwise cryptogenic stroke or TIA Aspirin

• Atrial fibrillation OAC

Mitral annular calcification

• Without atrial fibrillation but systemic

embolization, or otherwise cryptogenic

stroke or TIA

Aspirin

• Recurrent embolization despite aspirin OAC

• With atrial fibrillation OAC

Aortic valve calcification

• Asymptomatic No therapy

• Otherwise cryptogenic stroke or TIA Aspirin

Aortic arch mobile atheroma

• Otherwise cryptogenic stroke or TIA Aspirin or OAC

Patent foramen ovale

• Otherwise cryptogenic ischemic stroke

or TIA

Aspirin or closure with device

• Indication for OAC (deep-venous

thrombosis or hypercoagulable state)

OAC

Mechanical heart value

• Aortic position, bileaflet or Medtronic Hall

tilting disk with normal left atrial size and

sinus rhythm

VKA INR 2.5, range 2–3

• Mitral position tilting disk or bileaflet valve VKA INR 3.0, range 2.5–3.5

• Mitral or aortic position, anterior-apical

myocardial infarct or left atrial enlargement

VKA INR 3.0, range 2.5–3.5

• Mitral or aortic position, with atrial

fibrillation, or hypercoagulable state, or

low ejection fraction, or atherosclerotic

vascular disease

Aspirin plus VKA INR 3.0,

range 2.5–3.5

• Systemic embolization despite target INR Add aspirin and/or increase

INR: prior target was 2.5,

increase to 3.0, range 2.5–3.5;

prior target was 3.0, increase to

3.5, range 3–4

Bioprosthetic valve

• No other indication for VKA therapy Aspirin

Infective endocarditis Avoid antithrombotic agents

Nonbacterial thrombotic endocarditis

• With systemic embolization Full-dose, unfractionated

heparin or SC LMWH, or Xa

inhibitor

a

CHA2

DS2

-VASc score is calculated as follows: 1 point for congestive heart failure,

1 point for hypertension, 2 points for age ≥75 years, 1 point for diabetes mellitus,

2 points for stroke or TIA, 1 point for vascular disease (prior myocardial infarction,

peripheral vascular disease, or aortic plaque), 1 point for age 65–74 years, 1 point

for female sex category; sum of points is the total CHA2

DS2

-VASc score.

Note: Dose of aspirin is 50–325 mg/d; target INR for VKA is between 2 and 3 unless

otherwise specified.

Abbreviations: INR, international normalized ratio; LMWH, low-molecular-weight

heparin; OAC, oral anticoagulant (VKA, thrombin inhibitor, or oral factor Xa

inhibitors); TIA, transient ischemic attack; VKA, vitamin K antagonist.

Sources: Data from DE Singer et al: Chest 133:546S, 2008; DN Salem et al: Chest

133:593S, 2008; CT January et al: JACC 64:2246, 2014.

a stroke or TIA within the vascular distribution of the artery, and it is

associated with a greater risk of subsequent stroke than asymptomatic stenosis, in which the patient is symptom free and the stenosis is

detected through screening. Greater degrees of arterial narrowing are

generally associated with a higher risk of stroke, except that those with

near occlusions are at lower risk of stroke.

OTHER CAUSES OF ARTERY-TO-ARTERY EMBOLIC STROKE Intracranial

atherosclerosis produces stroke either by an embolic mechanism or by

in situ thrombosis of a diseased vessel. It is more common in patients

of Asian and African-American descent. Recurrent stroke risk is ~15%

per year, similar to untreated symptomatic carotid atherosclerosis.

Dissection of the internal carotid or vertebral arteries or even vessels

beyond the circle of Willis is a common source of embolic stroke in

young (age <60 years) patients. The dissection is usually painful and

precedes the stroke by several hours or days. Extracranial dissections

do not cause hemorrhage, presumably because of the tough adventitia

of these vessels. Intracranial dissections, conversely, may produce

SAH because the adventitia of intracranial vessels is thin and pseudoaneurysms may form, requiring urgent treatment to prevent rerupture. Treating asymptomatic pseudoaneurysms following extracranial

dissection is likely not necessary. The cause of dissection is usually

unknown, and recurrence is rare. Ehlers-Danlos type IV, Marfan’s

disease, cystic medial necrosis, and fibromuscular dysplasia are associated with dissections. Trauma (usually a motor vehicle accident or a

sports injury) can cause carotid and vertebral artery dissections. Spinal

manipulative therapy is associated with vertebral artery dissection

and stroke. Most dissections heal spontaneously, and stroke or TIA is

uncommon beyond 2 weeks. One trial showed no difference in stroke

prevention with aspirin compared to anticoagulation, with a low recurrent stroke rate of 2%.

■ SMALL-VESSEL STROKE

The term lacunar infarction refers to infarction following atherothrombotic or lipohyalinotic occlusion of a small artery in the brain. The

term small-vessel stroke denotes occlusion of such a small penetrating

artery and is now the preferred term. Small-vessel strokes account for

~20% of all strokes.

Pathophysiology The MCA stem, the arteries comprising the

circle of Willis (A1 segment, anterior and posterior communicating

arteries, and P1 segment), and the basilar and vertebral arteries all give

rise to 30- to 300-μm branches that penetrate the deep gray and white

matter of the cerebrum or brainstem (Fig. 427-4). Each of these small

branches can occlude either by atherothrombotic disease at its origin or

by the development of lipohyalinotic thickening. Thrombosis of these

vessels causes small infarcts that are referred to as lacunes (Latin for

“lake” of fluid noted at autopsy). These infarcts range in size from 3 mm

to 2 cm in diameter. Hypertension and age are the principal risk factors.

Clinical Manifestations The most common small-vessel stroke

syndromes are the following: (1) pure motor hemiparesis from an

infarct in the posterior limb of the internal capsule or the pons; the

face, arm, and leg are almost always involved; (2) pure sensory stroke

from an infarct in the ventral thalamus; (3) ataxic hemiparesis from an

infarct in the ventral pons or internal capsule; (4) and dysarthria and a

clumsy hand or arm due to infarction in the ventral pons or in the genu

of the internal capsule.

Transient symptoms (small-vessel TIAs) may herald a small-vessel

infarct; they may occur several times a day and last only a few minutes.

Recovery from small-vessel strokes tends to be more rapid and complete than recovery from large-vessel strokes; in some cases, however,

there is severe permanent disability.

A large-vessel source (either thrombosis or embolism) may manifest

initially as a small-vessel infarction. Therefore, the search for embolic

sources (carotid and heart) should not be completely abandoned in

the evaluation of these patients. Secondary prevention of small-vessel

stroke involves risk factor modification, specifically reduction in blood

pressure (see “Treatment: Primary and Secondary Prevention of Stroke

and TIA,” below).

3342 PART 13 Neurologic Disorders

TABLE 427-4 Risk Factors for Stroke

RISK FACTOR RELATIVE RISK RELATIVE RISK REDUCTION WITH TREATMENT

NUMBER NEEDED TO TREATa

PRIMARY PREVENTION SECONDARY PREVENTION

Hypertension 2–5 38% 100–300 50–100

Atrial fibrillation 1.8–2.9 68% warfarin, 21% aspirin 20–83 13

Diabetes 1.8–6 No proven effect

Smoking 1.8 50% at 1 year, baseline risk at 5 years

postcessation

Hyperlipidemia 1.8–2.6 16–30% 560 230

Asymptomatic carotid stenosis 2.0 53% 85 N/A

Symptomatic carotid stenosis

(70–99%)

65% at 2 years N/A 12

Symptomatic carotid stenosis

(50–69%)

29% at 5 years N/A 77

a

Number needed to treat to prevent one stroke annually. Prevention of other cardiovascular outcomes is not considered here.

Abbreviation: N/A, not applicable.

Anterior cerebral a.

Anterior cerebral a.

Internal carotid a.

Basilar a.

Basilar a.

Vertebral a.

Vertebral a.

Internal

carotid a.

Middle cerebral a.

Deep branches

of the basilar a.

Middle cerebral a.

Deep branches of the

middle cerebral a.

FIGURE 427-4 Diagrams and reformatted computed tomography (CT) angiograms in the coronal section illustrating

the deep penetrating arteries involved in small-vessel strokes. In the anterior circulation, small penetrating

arteries called lenticulostriates arise from the proximal portion of the anterior and middle cerebral arteries and

supply deep subcortical structures (upper panels). In the posterior circulation, similar arteries arise directly from

the vertebral and basilar arteries to supply the brainstem (lower panels). Occlusion of a single penetrating artery

gives rise to a discrete area of infarct (pathologically termed a “lacune,” or lake). Note that these vessels are too

small to be visualized on CT angiography.

■ LESS COMMON CAUSES OF STROKE

(Table 427-2) Hypercoagulable disorders (Chap. 65) primarily increase

the risk of cortical vein or cerebral venous sinus thrombosis. Systemic

lupus erythematosus with Libman-Sacks endocarditis can be a cause

of embolic stroke. These conditions overlap with the antiphospholipid

syndrome (Chap. 357), which probably requires long-term anticoagulation to prevent further stroke. Homocysteinemia may cause arterial

thromboses as well; this disorder is caused by various mutations in the

homocysteine pathways and responds to different forms of cobalamin depending on the

mutation. Disseminated intravascular coagulopathy can cause both venous and arterial

occlusive events; COVID-19 infection may

predispose for acute ischemic stroke due to

large-vessel occlusion.

Venous sinus thrombosis of the lateral or

sagittal sinus or of small cortical veins (cortical vein thrombosis) occurs as a complication

of oral contraceptive use, pregnancy and the

postpartum period, inflammatory bowel disease, intracranial infections (meningitis), and

dehydration. It is also seen in patients with

laboratory-confirmed thrombophilia including antiphospholipid syndrome, polycythemia, sickle cell anemia, deficiencies of proteins

C and S, factor V Leiden mutation (resistance to activated protein C), antithrombin III

deficiency, homocysteinemia, and the prothrombin G20210 mutation. Women who take

oral contraceptives and have the prothrombin

G20210 mutation may be at particularly high

risk for sinus thrombosis. Patients present

with headache and may also have focal neurologic signs (especially paraparesis) and seizures. Often, CT imaging is normal unless an

intracranial venous hemorrhage has occurred,

but the venous sinus occlusion is readily visualized using MR or CT venography or conventional x-ray angiography. With greater degrees

of sinus thrombosis, the patient may develop

signs of increased ICP and coma. Intravenous

heparin, regardless of the presence of intracranial hemorrhage, reduces morbidity and

mortality, and the long-term outcome is generally good. Heparin prevents further thrombosis and reduces venous hypertension and

ischemia. If an underlying hypercoagulable

state is not found, many physicians treat with

oral anticoagulants for 3–6 months and then

convert to aspirin, depending on the degree

of resolution of the venous sinus thrombus.

Anticoagulation is often continued indefinitely if thrombophilia is diagnosed.

3343 Ischemic Stroke CHAPTER 427

Sickle cell anemia (SS disease) is a common cause of stroke in children. A subset of homozygous carriers of this hemoglobin mutation

develop stroke in childhood, and this may be predicted by documenting high-velocity blood flow within the MCAs using transcranial

Doppler ultrasonography. In children who are identified to have high

velocities, treatment with aggressive exchange transfusion dramatically

reduces risk of stroke, and if exchange transfusion is ceased, their

stroke rate increases again along with MCA velocities.

Fibromuscular dysplasia (Chap. 281) affects the cervical arteries

and occurs mainly in women. The carotid or vertebral arteries show

multiple rings of segmental narrowing alternating with dilatation.

Vascular occlusion is usually incomplete. The process is often asymptomatic but occasionally is associated with an audible bruit, TIAs, or

stroke. Involvement of the renal arteries is common and may cause

hypertension. The cause and natural history of fibromuscular dysplasia

are unknown. TIA or stroke generally occurs only when the artery is

severely narrowed or dissects. Anticoagulation or antiplatelet therapy

may be helpful.

Temporal (giant cell) arteritis (Chap. 363) is a relatively common

affliction of elderly individuals in which the external carotid system,

particularly the temporal arteries, undergoes subacute granulomatous

inflammation with giant cells. Occlusion of posterior ciliary arteries

derived from the ophthalmic artery results in blindness in one or both

eyes and can be prevented with glucocorticoids. It rarely causes stroke

because the internal carotid artery is usually not inflamed. Idiopathic

giant cell arteritis involving the great vessels arising from the aortic

arch (Takayasu’s arteritis) may cause carotid or vertebral thrombosis; it

is rare in the Western Hemisphere.

Necrotizing (or granulomatous) arteritis (Chap. 363), occurring

alone or in association with generalized polyarteritis nodosa or granulomatosis with polyangiitis (Wegener’s), involves the distal small

branches (<2 mm diameter) of the main intracranial arteries and

produces small ischemic infarcts in the brain, optic nerve, and spinal

cord. The CSF often shows pleocytosis, and the protein level is elevated.

Primary central nervous system vasculitis is rare; small or mediumsized vessels are usually affected, without apparent systemic vasculitis.

The differential diagnosis includes other inflammatory vasculopathies

including infection (tuberculous, fungal), sarcoidosis, angiocentric

lymphoma, carcinomatous meningitis, and noninflammatory causes

such as atherosclerosis, emboli, connective tissue disease, vasospasm,

migraine-associated vasculopathy, and drug-associated causes. Some

cases develop in the postpartum period and are self-limited.

Patients with any form of vasculopathy may present with insidious

progression of combined white and gray matter infarctions, prominent

headache, and cognitive decline. Brain biopsy or high-resolution conventional x-ray angiography is usually required to make the diagnosis

(Fig. 427-5). A lumbar puncture (elevated white blood cells, elevated

IgG index, bands on electrophoresis) can provide support for an

inflammatory etiology of a neurovascular problem. When inflammation is confirmed, aggressive immunosuppression with glucocorticoids,

and often cyclophosphamide, is usually necessary to prevent progression; a diligent investigation for infectious causes such as tuberculosis

is essential prior to immunosuppression. With prompt recognition and

treatment, many patients can make an excellent recovery.

Drugs, in particular amphetamines and perhaps cocaine, may cause

stroke on the basis of acute hypertension or drug-induced vasculopathy. This vasculopathy is commonly due to vasospasm or atherosclerosis, but cases of inflammatory vasculitis have also been reported. No

data exist on the value of any treatment, but cessation of stimulants

is prudent. Phenylpropanolamine has been linked with intracranial

hemorrhage, as has cocaine and methamphetamine, perhaps related

to a drug-induced vasculopathy. Moyamoya disease is a poorly understood occlusive disease involving large intracranial arteries, especially

the distal internal carotid artery and the stem of the MCA and ACA.

Vascular inflammation is absent. The lenticulostriate arteries develop

a rich collateral circulation around the occlusive lesion, which gives

the impression of a “puff of smoke” (moyamoya in Japanese) on

conventional x-ray angiography. Other collaterals include transdural

anastomoses between the cortical surface branches of the meningeal

and scalp arteries. The disease occurs mainly in Asian children or

young adults, but the appearance may be identical in adults who have

atherosclerosis, particularly in association with diabetes. Intracranial

hemorrhage may result from rupture of the moyamoya collaterals;

thus, anticoagulation is risky. Progressive occlusion of large surface

arteries can occur, producing large-artery distribution strokes. Surgical

bypass of extracranial carotid arteries to the dura or MCAs may prevent stroke and hemorrhage.

Posterior reversible encephalopathy syndrome (PRES) can occur

with head injury, seizure, migraine, sympathomimetic drug use,

and eclampsia and in the postpartum period. The pathophysiology

is uncertain but likely involves a hyperperfusion state where blood

pressure exceeds the upper limit of cerebral autoregulation resulting

in cerebral edema (Chap. 307). Patients complain of headache and

manifest fluctuating neurologic symptoms and signs, especially visual

symptoms. Sometimes cerebral infarction ensues, but typically, the

clinical and imaging findings reverse completely. MRI findings are

characteristic with the edema present within the occipital lobes but

can be generalized and do not respect any single vascular territory. A

closely related reversible cerebral vasoconstriction syndrome (RCVS)

typically presents with sudden, severe headache closely mimicking

SAH. Patients may experience ischemic infarction and intracerebral

hemorrhage and typically have new-onset, severe hypertension. Conventional x-ray angiography reveals changes in the vascular caliber

throughout the hemispheres resembling vasculitis, but the process is

noninflammatory. Oral calcium channel blockers may be effective in

producing remission, and recurrence is rare.

Leukoaraiosis, or periventricular white matter disease, is the result

of multiple small-vessel infarcts within the subcortical white matter.

It is readily seen on CT or MRI scans as areas of white matter injury

surrounding the ventricles and within the corona radiata. The pathophysiologic basis of the disease is lipohyalinosis of small penetrating

arteries within the white matter, likely produced by chronic hypertension. Patients with periventricular white matter disease may develop

a subcortical dementia syndrome, and it is likely that this common

form of dementia may be delayed or prevented with antihypertensive

medications (Chap. 433).

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is an inherited disorder that

presents as small-vessel strokes, progressive dementia, and extensive

symmetric white matter changes often including the anterior temporal

lobes visualized by MRI. Approximately 40% of patients have migraine

with aura, often manifest as transient motor or sensory deficits. Onset

is usually in the fourth or fifth decade of life. This autosomal dominant

condition is caused by one of several mutations in Notch-3, a member

of a highly conserved gene family characterized by epidermal growth

factor repeats in its extracellular domain. Other monogenic ischemic

FIGURE 427-5 Cerebral angiogram from a 32-year-old male with central nervous

system vasculopathy. Dramatic beading (arrows) typical of vasculopathy is seen.

3344 PART 13 Neurologic Disorders

stroke syndromes include cerebral autosomal recessive arteriopathy

with subcortical infarcts and leukoencephalopathy (CARASIL) and

hereditary endotheliopathy, retinopathy, nephropathy, and stroke

(HERNS). Fabry’s disease also produces both a large-vessel arteriopathy and small-vessel infarctions. The COL4A1 mutation is associated

with multiple small-vessel strokes with hemorrhagic transformation.

■ TRANSIENT ISCHEMIC ATTACKS

TIAs are episodes of stroke symptoms that last only briefly; the standard definition of duration is <24 h, but most TIAs last <1 h. If a relevant brain infarction is identified on brain imaging, the clinical entity is

now classified as stroke regardless of the duration of symptoms. A normal brain imaging study following a TIA does not rule out TIA; rather,

the clinical syndrome is diagnostic. The causes of TIA are similar to

the causes of ischemic stroke, but because TIAs may herald stroke,

they are an important risk factor that should be considered separately

and urgently. TIAs may arise from emboli to the brain or from in situ

thrombosis of an intracranial vessel. With a TIA, the occluded blood

vessel reopens and neurologic function is restored.

The risk of stroke after a TIA is ~10–15% in the first 3 months, with

most events occurring in the first 2 days. This risk can be directly estimated using the well-validated ABCD2

 score (Table 427-5). Therefore,

urgent evaluation and treatment are justified. Because etiologies for

stroke and TIA are identical, evaluation for TIA should parallel that

of stroke.

TREATMENT

Transient Ischemic Attack

The improvement characteristic of TIA is a contraindication to

thrombolysis. However, because the risk of subsequent stroke in

the first few hours and days following TIA is high, some physicians

admit the patient to the hospital so a plasminogen activator can

be rapidly administered if symptoms return. The combination of

aspirin and clopidogrel was found to prevent stroke following TIA

better than aspirin alone in a large Chinese randomized trial and

the National Institutes of Health (NIH)–sponsored trial (POINT

study). Failure to respond to the combination of aspirin and clopidogrel is linked to carriage of a common CYP2C19 polymorphism

that leads to poor metabolism of clopidogrel into its active form.

This mutation is common, particularly in Asians. Recently, ticagrelor, 180-mg loading dose and then 90 mg twice daily, was tested in

combination with aspirin compared to aspirin alone, and this also

showed benefit in preventing stroke; this dual antiplatelet regimen

may be favored because of the lack of genetic heterogeneity in

platelet inhibition.

Primary and Secondary Prevention of

Stroke and TIA

GENERAL PRINCIPLES

Many medical and surgical interventions, as well as lifestyle modifications, are available for preventing stroke. Some of these can be

widely applied because of their low cost and minimal risk; others

are expensive and carry substantial risk but may be valuable for

selected high-risk patients. Identification and control of modifiable

risk factors, and especially hypertension, is the best strategy to

reduce the burden of stroke, and the total number of strokes could

be reduced substantially by these means (Table 427-4).

ATHEROSCLEROSIS RISK FACTORS

The relationship of various factors to the risk of atherosclerosis

is described in Chaps. 237 and 238. Older age, diabetes mellitus, hypertension, tobacco smoking, abnormal blood cholesterol

(particularly, low high-density lipoprotein [HDL] and/or elevated

low-density lipoprotein [LDL]), lipoprotein (a) excess, and other

factors are either proven or probable risk factors for ischemic

stroke, largely by their link to atherosclerosis. Risk of stroke is much

greater in those with prior stroke or TIA. Many cardiac conditions

predispose to stroke, including atrial fibrillation and recent MI.

Oral contraceptives and hormone replacement therapy increase

stroke risk, and although rare, certain inherited and acquired

hypercoagulable states predispose to stroke.

Hypertension is the most significant of the risk factors; in general,

all hypertension should be treated to a target of <130/80 mmHg.

Recent data (the Systolic Blood Pressure Intervention Trial—

SPRINT) suggest that lowering systolic blood pressure <120 mmHg

reduces stroke and heart attack by 43% compared to systolic blood

pressure <140 mmHg, without an increased risk of syncope or falls.

The presence of known cerebrovascular disease is not a contraindication to treatment aimed at achieving normotension. Data are

particularly strong in support of thiazide diuretics and angiotensinconverting enzyme inhibitors.

Several trials have confirmed that statin drugs reduce the risk

of stroke even in patients without elevated LDL or low HDL. The

Stroke Prevention by Aggressive Reduction in Cholesterol Levels

(SPARCL) trial showed benefit in secondary stroke reduction for

patients with recent stroke or TIA who were prescribed atorvastatin,

80 mg/d. The primary prevention trial, Justification for the Use of

Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER), found that patients with low LDL (<130 mg/dL)

caused by elevated C-reactive protein benefitted by daily use of

this statin. Primary stroke occurrence was reduced by 51% (hazard

ratio, 0.49; p = .004), and there was no increase in the rates of intracranial hemorrhage. Meta-analysis has also supported a primary

treatment effect for statins given acutely for ischemic stroke. A

serum LDL <70 mg/dL lowers recurrent stroke risk better than an

LDL of 90–110 mg/dL. Therefore, a statin should be considered in

all patients with prior ischemic stroke. Tobacco smoking should

be discouraged in all patients (Chap. 454). The use of pioglitazone

(an agonist of peroxisome proliferator-activated receptor gamma)

in patients with type 2 diabetes and previous stroke does not lower

stroke, MI, or vascular death rates but is effective in lowering vascular events in patients with stroke and prediabetes or insulin resistance alone. Diabetes prevention is likely the most effective strategy

for primary and secondary stroke prevention.

TABLE 427-5 Risk of Stroke Following Transient Ischemic Attack:

The ABCD2

 Score

CLINICAL FACTOR SCORE

A: Age ≥60 years 1

B: SBP >140 mmHg or DBP >90 mmHg 1

C: Clinical symptoms

Unilateral weakness 2

Speech disturbance without weakness 1

D: Duration

>60 min 2

10–59 min 1

D: Diabetes (oral medications or insulin) 1

TOTAL SCORE SUM EACH CATEGORY

ABCD2

 Score Total 3-Month Rate of Stroke (%)a

0 0

1 2

2 3

3 3

4 8

5 12

6 17

7 22

a

Data ranges are from five cohorts.

Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure.

Source: Data from SC Johnston et al: Validation and refinement of scores to predict

very early stroke risk after transient ischaemic attack. Lancet 369:283, 2007.

3345 Ischemic Stroke CHAPTER 427

ANTIPLATELET AGENTS FOR STROKE PREVENTION

Platelet antiaggregation agents can prevent atherothrombotic events,

including TIA and stroke, by inhibiting the formation of intraarterial platelet aggregates. These can form on diseased arteries,

induce thrombus formation, and occlude or embolize into the distal

circulation. Aspirin, clopidogrel, the combination of aspirin plus

extended-release dipyridamole, and recently ticagrelor are the antiplatelet agents most commonly used for this purpose. Ticagrelor

has not been found to be better than aspirin for stroke prevention

except in combination with aspirin following TIA.

Aspirin is the most widely studied antiplatelet agent. Aspirin

acetylates platelet cyclooxygenase, which irreversibly inhibits the

formation in platelets of thromboxane A2

, a platelet aggregating and

vasoconstricting prostaglandin. This effect is permanent and lasts

for the usual 8-day life of the platelet. Paradoxically, aspirin also

inhibits the formation in endothelial cells of prostacyclin, an antiaggregating and vasodilating prostaglandin. This effect is transient. As

soon as aspirin is cleared from the blood, the nucleated endothelial

cells again produce prostacyclin. Aspirin in low doses given once

daily inhibits the production of thromboxane A2

 in platelets without substantially inhibiting prostacyclin formation. Higher doses of

aspirin have not been proven to be more effective than lower doses.

Clopidogrel and ticagrelor block the adenosine diphosphate

(ADP) receptor on platelets and thus prevent the cascade resulting in activation of the glycoprotein IIb/IIIa receptor that leads to

fibrinogen binding to the platelet and consequent platelet aggregation. Clopidogrel can cause rash and, in rare instances, thrombotic

thrombocytopenic purpura. The Clopidogrel versus Aspirin in

Patients at Risk of Ischemic Events (CAPRIE) trial, which led to

U.S. Food and Drug Administration (FDA) approval, found that

it was only marginally more effective than aspirin in reducing risk

of stroke. The Management of Atherothrombosis with Clopidogrel in High-Risk Patients (MATCH) trial was a large multicenter, randomized, double-blind study that compared clopidogrel in

combination with aspirin to clopidogrel alone in the secondary

prevention of TIA or stroke. The MATCH trial found no difference

in TIA or stroke prevention with this combination but did show

a small but significant increase in major bleeding complications

(3 vs 1%). In the Clopidogrel for High Atherothrombotic Risk and

Ischemic Stabilization, Management, and Avoidance (CHARISMA)

trial, which included a subgroup of patients with prior stroke or

TIA along with other groups at high risk of cardiovascular events,

there was no benefit of clopidogrel combined with aspirin compared to aspirin alone. Lastly, the SPS3 trial looked at the long-term

combination of clopidogrel and aspirin versus clopidogrel alone in

small-vessel stroke and found no improvement in stroke prevention

and a significant increase in both hemorrhage and death. Thus, the

long-term use of clopidogrel in combination with aspirin is not

recommended for stroke prevention.

The short-term combination of clopidogrel with aspirin may

be effective in preventing second stroke, however. A large trial of

Chinese patients enrolled within 24 h of TIA or minor ischemic

stroke found that a clopidogrel-aspirin regimen (clopidogrel

300 mg load then 75 mg/d with aspirin 75 mg for the first 21 days)

was superior to aspirin (75 mg/d) alone, with 90-day stroke risk

decreased from 11.7 to 8.2% (p <.001) and no increase in major

hemorrhage. This benefit was limited to those not carrying the

CYP2C19 polymorphism associated with clopidogrel hypometabolism. An international NIH-sponsored trial demonstrated similar

results; therefore, the combination of aspirin and clopidogrel should

be administered for TIA or minor ischemic stroke for the first

21–90 days before switching to monotherapy.

A recent study of oral ticagrelor plus aspirin versus aspirin alone

has shown similar benefits in secondary stroke reduction and carries the likely advantage that ticagrelor’s antiplatelet effect is not

genetically variable, as is the case with clopidogrel.

Dipyridamole is an antiplatelet agent that inhibits the uptake

of adenosine by a variety of cells, including those of the vascular endothelium. The accumulated adenosine is an inhibitor of

aggregation. At least in part through its effects on platelet and

vessel wall phosphodiesterases, dipyridamole also potentiates the

antiaggregatory effects of prostacyclin and nitric oxide produced

by the endothelium and acts by inhibiting platelet phosphodiesterase, which is responsible for the breakdown of cyclic AMP.

The resulting elevation in cyclic AMP inhibits aggregation of platelets. Dipyridamole is erratically absorbed depending on stomach

pH, but a newer formulation combines timed-release dipyridamole,

200 mg, with aspirin, 25 mg, and has better oral bioavailability.

This combination drug was studied in three trials. The European

Stroke Prevention Study (ESPS) II showed efficacy of both

50 mg/d of aspirin and extended-release dipyridamole in preventing stroke and a significantly better risk reduction when the

two agents were combined. The open-label ESPRIT (European/

Australasian Stroke Prevention in Reversible Ischaemia Trial) trial

confirmed the ESPS-II results. After 3.5 years of follow-up, 13%

of patients on aspirin and dipyridamole and 16% on aspirin alone

(hazard ratio, 0.80; 95% CI, 0.66–0.98) met the primary outcome of

death from all vascular causes. In the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial, the combination of

extended-release dipyridamole and aspirin was compared directly

with clopidogrel with and without the angiotensin receptor blocker

telmisartan; there were no differences in the rates of second stroke

(9% each) or degree of disability in patients with median follow-up

of 2.4 years. Telmisartan also had no effect on these outcomes. This

suggests that these antiplatelet regimens are similar and raises questions about default prescription of agents to block the angiotensin

pathway in all stroke patients. The principal side effect of dipyridamole is headache. The combination capsule of extended-release

dipyridamole and aspirin is approved for prevention of stroke.

Many large clinical trials have demonstrated clearly that most

antiplatelet agents reduce the risk of all important vascular atherothrombotic events (i.e., ischemic stroke, MI, and death due to all vascular causes) in patients at risk for these events. The overall relative

reduction in risk of nonfatal stroke is ~25–30% and of all vascular

events is ~25%. The absolute reduction varies considerably, depending on the patient’s risk. Individuals at very low risk for stroke seem

to experience the same relative reduction, but their risks may be so

low that the “benefit” is meaningless. Conversely, individuals with

a 10–15% risk of vascular events per year experience a reduction

to ~7.5–11%.

Aspirin is inexpensive, can be given in low doses, and could

be recommended for all adults to prevent both stroke and MI.

However, it causes epigastric discomfort, gastric ulceration, and

gastrointestinal hemorrhage, which may be asymptomatic or life

threatening. Consequently, not every 40- or 50-year-old should

be advised to take aspirin regularly because the risk of atherothrombotic stroke is extremely low and is outweighed by the risk of

adverse side effects. Conversely, every patient who has experienced

an atherothrombotic stroke or TIA and has no contraindication to

antiplatelet therapy (or indication for anticoagulation) should be

taking an antiplatelet agent regularly because the average annual

risk of another stroke is 8–10%; another few percent will experience

an MI or vascular death. Clearly, the likelihood of benefit far outweighs the risks of treatment.

The choice of antiplatelet agent and dose must balance the risk of

stroke, the expected benefit, and the risk and cost of treatment. However, there are no definitive data, and opinions vary. Many authorities believe low-dose (30–75 mg/d) and high-dose (650–1300 mg/d)

aspirin are about equally effective. Some advocate very low doses to

avoid adverse effects, and still others advocate very high doses to

be sure the benefit is maximal. Most physicians in North America

recommend 81–325 mg/d, whereas most Europeans recommend

50–100 mg. Clopidogrel and extended-release dipyridamole plus

aspirin are being increasingly recommended as first-line drugs for

secondary prevention. Similarly, the choice of aspirin, clopidogrel,

or dipyridamole plus aspirin must balance the fact that the latter are

more effective than aspirin but the cost is higher, and this is likely to

affect long-term patient adherence. The use of platelet aggregation