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Definitions

TRANSIENT ISCHEMIC ATTACK

A transient ischemic attack (TIA) is now defined as transient episode of neurologic

dysfunction caused by focal brain, spinal cord, or retinal ischemia not associated

with permanent cerebral infarction.

2

It used to be described as the clinical condition

in which a patient experiences a temporary (lasting less than 24 hours) focal

neurologic deficit such as slurred speech, aphasia, weakness or paralysis of a limb,

or blindness. However, the original description is no longer valid because it is

implied that TIAs are minor and that symptoms disappeared completely, while recent

studies and imaging techniques have shown that TIA can actually lead to brain injury

and increased risk of recurrent stroke. Some would argue that TIA term should not be

even used at all.

ISCHEMIC STROKE

Ischemic stroke is defined as an infarction of the CNS. Unlike TIAs, ischemic stroke

may be either symptomatic or silent.

2 Clinical signs of focal or global cerebral,

spinal or retinal dysfunction caused by a CNS infarction are the manifestation of a

symptomatic stroke. The two primary causes of infarction and persistent ischemia are

atherosclerosis of cerebral blood vessels or an embolus to the cerebral arteries from

a distant clot.

INTRACRANIAL HEMORRHAGE

Intracranial hemorrhage involves movement of blood from blood vessels inside the

brain into the brain tissue, or parenchyma, and its surrounding structures. Clinical

symptoms associated with intracranial hemorrhage are similar to but often more

severe than those because of ischemic strokes. These symptoms commonly include

neurologic deficits as well as headache, vomiting, and a decreased level of

consciousness. Some patients may experience other symptoms including seizures,

EKG abnormalities, and a stiff neck. Depending on the type and size of intracranial

hemorrhage, symptoms may develop abruptly or worsen slowly over minutes to

hours.

The location of the hemorrhage within the intracranial vault determines the type of

intracranial hemorrhage. Intracerebral hemorrhages (ICHs) occur when blood moves

into the brain parenchyma, whereas other types of hemorrhages develop when blood

moves into spaces around the brain tissue.

Epidemiology

Each year an estimated 795,000 individuals in the United States experience a new or

recurrent stroke and approximately 610,000 of these are first attacks. It is the fourth

most common cause of death in adults after diseases of the heart, cancer, and chronic

lower respiratory disease. There is a higher regional incidence and prevalence of

stroke and a higher stroke mortality rate in the southern United States than in the rest

of the country. Younger men have a higher incidence of stroke than women in the

same age group; however, in age group >75 years, women have a higher incidence.

Blacks and Hispanics have an increased risk of stroke compared with whites in the

United States. The precise reasons for these differences are unclear, but genetic,

geographic, dietary, and cultural factors have been considered.

3

In addition, the

incidence of risk factors for stroke such as hypertension, diabetes, and

hypercholesterolemia differs among racial groups.

In the United States ischemic stroke is the most common type of infarction (Fig.

61-1). Atherothrombotic disease of the large cerebral blood vessels is responsible

for the majority of cerebral ischemic events and infarctions. Disease of penetrating

arteries that are responsible for oxygenation and nutrition of the CNS,

thromboembolic causes (e.g., atrial fibrillation), and other causes such as infection or

inflammation of arteries are also responsible for ischemic stroke.

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Table 61-1

Risk Factors for Transient Ischemic Attack and Ischemic Stroke

Modifiable Potentially Modifiable Non-modifiable

Cardiovascular disease (coronary

heart disease, heart failure,

peripheral arterial disease)

Hypertension

Cigarette smoking

Diabetes

Asymptomatic carotid stenosis

Atrial fibrillation

Sickle cell disease

Metabolic syndrome

Alcohol abuse (≥5 drinks daily)

Hyperhomocysteinemia

Drug abuse (e.g., cocaine,

amphetamine, methamphetamine)

Hypercoagulability (e.g.,

anticardiolipin, factor V Leiden,

protein C deficiency, protein S

deficiency, antithrombin III

deficiency)

Age (doubling each 10 years after

age 55)

Race (blacks > Hispanics > whites)

Sex (men > women)

Low birth weight (<2,500 g)

Family history of stroke (paternal >

maternal)

Dyslipidemia (high total cholesterol,

low HDL)

Oral contraceptive use (women 25–

44 years old)

Dietary factors (sodium intake

<2,300 mg/day; potassium intake

<4,700 mg/day)

Inflammatory processes (e.g.,

periodontal disease,

cytomegalovirus, Helicobacter

pyloriseropositive)

Obesity

Physical inactivity

Acute infection (e.g., respiratory

infection, urinary tract infection)

Postmenopausal hormone therapy

(women 50–74 years old)

CD40 ligand >3.71 ng/mL in

women free of cardiovascular

disease

IL-18 upper tertile

hs-CRP >3 mg/L in women 45

years or older

Migraine headaches

High Lp(a)

High Lp-PLA2

Sleep-disordered breathing

HDL, high-density lipoprotein; hs-CRP, high-sensitivity C-reactive protein; IL, interleukin; Lp(a), lipoprotein(a);

Lp-LPA2

, lipoprotein-associated phospholipase A2

.

Source: Meschia JF et al. Guidelines for the primary prevention of stroke: a statement for healthcare professionals

from the American Heart Association/American Stroke Association. Stroke. 2014;45:3754.

There is a strong relationship between the occurrence of TIA and an increased risk

for subsequent cerebral infarction.

1

,

2 The risk of an ischemic stroke is highest in the

first 30 days after a TIA, and the risk within 90 days of a TIA is 3% to 17.3%.

Additionally, nearly 25% of patients who experience a TIA will die within a year.

2

Risk factors for cerebral infarction are listed in Table 61-1. Risk factors for stroke

are classified as either non-modifiable (e.g., age, race, gender) and modifiable if they

can be altered (e.g., hypertension, high cholesterol level, smoking). Cerebral infarct

prevention efforts will be focused on elimination and control of the modifiable risk

factors.

4

,

5 The control of risk factors is of primary importance in managing a patient

with a TIA or cerebral infarction.

Intracerebral hemorrhages account for 10% of all strokes in North America, while

subarachnoid hemorrhage, most commonly resulting from cerebral artery aneurysms,

comprises 3% of all strokes. Hypertensive hemorrhage is the most common cause of

ICH, with 46% of ICHs resulting from hypertension. In fact, hypertension more than

doubles the risk of ICH. A number of medications including warfarin and other

anticoagulants, such as dabigatran, rivaroxaban, and apixaban, significantly

predispose patients to ICH. Less commonly, ICH may occur because of an

arteriovenous malformation (AVM), which is a clump of arteries and veins that are

intertwined, resulting in weakened blood vessel walls.

Pathophysiology

The neurologic sequelae of cerebral ischemia or infarction directly result from an

embolic or thrombotic source. A clot may form in the heart, along the wall of a major

blood vessel (e.g., aorta, carotid, or basilar artery), or in small arteries penetrating

deep into the brain. If the clot is located near the infarction, it is a thrombus;

however, when the clot has migrated to the brain from a distant source, it is an

embolus. Either can diminish or block blood flow to the affected area of the brain.

Disorders such as atrial fibrillation, mitral or aortic valve disease, patent foramen

ovale, or coagulopathies are associated with formation of clots that may embolize to

the brain.

Inflammatory mechanisms also contribute to the development of ischemia,

especially thrombotic lesions. Substances, such as C-reactive protein, a mediator of

inflammation, are elevated in patients with an acute stroke. Inflammation is thought to

enhance the development of thrombotic lesions and result in sudden, intermittent

occlusion of blood vessels. Disorders such as arteritis (Takayasu, Giant cell), and

Moyamoya syndrome are examples of diseases where inflammation plays an

important role for the development of brain ischemia.

Cerebral blood flow in the normal adult brain is 30 to 70 mL/100 g of brain

tissue/minute. When a thrombotic or embolic clot partially occludes a cerebral

artery, causing a reduction in blood flow to less than 20 mL/100 g/minute, various

compensatory mechanisms are activated. These include vasodilation and increased

oxygen extraction. If the artery is further occluded and cerebral blood flow is

reduced to less than 12 mL/100 g/minute, the affected neurons become sufficiently

anoxic to die within minutes (Fig. 61-2).

6 Rapid reestablishment of blood flow to the

ischemic area can delay, prevent, or limit the onset of infarction, improving the

outcome of the acute stroke.

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p. 1304

Figure 61-2 Physiologic effects of cerebral anoxia.

Ischemia in the brain usually involves a core or focal region of profound ischemia

that results in neuronal death. The extent of this region is dependent on the amount of

brain that is perfused directly by the blood vessel that becomes occluded. There is a

surrounding area of brain that becomes marginally ischemic with normal function

being disrupted. This region of marginal ischemia is frequently called the ischemic

penumbra. If ischemia continues, neurons in this region will die. However, if normal

blood flow is restored quickly, neurons in this area will survive.

When neurons become ischemic, excitatory neurotransmitters are released, causing

neurons to rapidly and repeatedly discharge. Increased neuronal activity results in

extreme metabolic demands, disrupts neuronal homeostasis, depletes stores of

adenosine triphosphate, and synergistically increases the effects of hypoxia.

Especially vulnerable to ischemic effects are neurons in the middle layers of the

cerebral cortex; portions of the hippocampus (CA1 and subiculum regions), a

structure running parallel to the parahippocampal gyrus; and Purkinje cells in the

cerebellum.

7 There is also a rapid intracellular influx of calcium. Both voltagedependent and chemical-dependent calcium channels are unable to act as a gate to

prevent the movement of calcium, owing to depletion of cellular energy sources.

Intracellular stores of calcium ions also are disrupted, causing release of calcium

into the cytoplasm. Increased concentration of calcium ions enhances phospholipase

and protease activity and increases reactive metabolites, such as superoxide and

hydroxide ions, and nitric oxide. This eventually causes neuronal death.

6

,

7

In

addition, lipolysis of cell membranes occurs in the presence of an accumulation of

neurotoxic free radicals.

Immediate therapeutic intervention is needed to limit and prevent permanent

neurologic damage from these rapidly occurring events.

INTRACRANIAL HEMORRHAGE

Intracranial hemorrhages occur because of weakened intracranial blood vessels,

elevated pressure inside the blood vessels, and anatomical abnormalities. Specific

causes include hypertension, cerebral amyloid angiopathy, brain tumors, anatomical

derangements such as AVMs, coagulopathies, and trauma. Pathophysiologic

mechanisms differ depending on whether the bleeding occurs outside the brain

parenchyma in the subarachnoid, epidural, or subdural space or within the

intracerebral space.

In subarachnoid hemorrhage, blood moves quickly into the cerebrospinal fluid

(CSF), causing an acute elevation of intracranial pressure (ICP). ICP refers to the

pressure inside the intracranial vault and may be elevated because of brain tissue

swelling, the development of a hematoma (collection of blood) inside the brain, or

other conditions. Blood may also migrate into the intraventricular space or into the

brain tissue.

8

,

9 Obstruction of CSF fluid reabsorption and movement out of the brain

because of the presence of blood in the brain can result in hydrocephalus, which is

the buildup of CSF within the ventricles of the brain. Delayed cerebral ischemia,

commonly referred to as “vasospasm” of the cerebral vasculature, may also

complicate subarachnoid hemorrhage.

Epidural and subdural hematomas are other types of intracranial hemorrhages that

occur outside the brain parenchyma. Depending on their size, epidural and subdural

hematomas may significantly compress and displace brain tissue, resulting in

elevated ICP and brain herniation because of mass effect. Brain herniation refers to

abnormal movement of brain tissue across structures inside the skull that occurs

because of elevated pressures within the intracranial vault. This squeezing of brain

tissue can significantly compress cerebral blood flow, consequently compromising

oxygen delivery to the brain and causing brain cells to die.

Spontaneous intracerebral hemorrhage because of hypertension develops in areas

of the brain where smaller blood vessels branch out from large blood vessels at 90

degree angles, exposing the smaller vessels to the higher pressure of the preceding

blood vessel and eventually resulting in bleeding of the smaller vessels.

10

In

intracerebral hemorrhage, the movement of blood from blood vessels into the brain

parenchyma causes local irritation of the brain tissue and edema. In the case of large

hemorrhages and significant edema, mass effect can ultimately increase ICP, reducing

blood flow to the brain and potentially causing brain tissue herniation.

11 Secondary

brain injury occurs in many patients after spontaneous ICH. It is caused by a

disrupted blood–brain barrier, release of inflammatory mediators, and progressive

edema that may last 7 to 12 days.

12–15

In spontaneous intracerebral hemorrhage, hematoma enlargement is associated

with poor outcomes. Non-modifiable risk factors for hematoma expansion are large

hematoma size and contrast extravasation on computed tomography (CT) at the time

of presentation, while potentially modifiable risk factors include coagulopathies and

ongoing uncontrolled hypertension after hospital admission.

16

,

17

General Treatment Principles

Rapid recognition of stroke symptoms and immediate initiation of treatment are

essential to the management of ischemic or hemorrhagic stroke. Appropriate

pharmacotherapy of stroke requires a precise diagnosis. It is vital to differentiate

between an ischemic stroke and a hemorrhagic stroke, because an inaccurate

diagnosis can lead to the use of drugs that may cause severe morbidity or mortality.

Interventions to prevent and treat ischemic strokes are directed at reducing risk

factors, eliminating or modifying the underlying pathologic process, and reducing

secondary brain damage. In hemorrhagic stroke, the emphasis of treatment is on

preventing hematoma expansion, managing intracranial pressure, and providing

supportive therapy to maximize neurologic function and minimize complications.

Rehabilitation is a key component of long-term care for many patients, regardless of

whether the stroke is ischemic or hemorrhagic.

PRIMARY PREVENTION OF ISCHEMIC STROKE

AND TRANSIENT ISCHEMIC ATTACKS

Risk Factors Modification

CASE 61-1

QUESTION 1: R.B. is a 60-year-old, 5 feet 6 inches tall, 85-kg woman who is concerned about having a

stroke. Her father died of a stroke, and her 85-year-old mother has had several episodes

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diagnosed as TIAs. R.B.’s blood pressure is 140 to 150/90 to 100 mm Hg, and she was recently diagnosed with

diabetes mellitus. She does not have a history of TIA or stroke. Additionally, she smoked for 25 years but has

not used tobacco for the past 10 years. Her current medications include lisinopril, metformin, conjugated

estrogen/medroxyprogesterone, and acetaminophen. She approaches her pharmacist because of concerns about

having a stroke and being “like her parents.” What can R.B. do to reduce her risk of stroke?

Any plan for primary prevention (i.e., prevention of a first event) of TIA or stroke

must address the control or reduction of risk factors (Table 61-2).The reader is

referred to a detailed discussion of treatment of diseases such as hypertension,

diabetes, coronary artery disease, chronic kidney disease, etc. in their respective

chapters (see Chapters 9, 13, 28, 53).

For R.B., hypertension is the most important and well-documented risk factor that

requires immediate attention.

4 Adequate control of her blood pressure should reduce

R.B.’s risk of stroke by 35% to 44%. On the basis of the eighth Report of the Joint

National Committee on Prevention, Detection, Evaluation, and Treatment of High

Blood Pressure (JNC-8) guidelines, R.B.’s blood pressure goal should be less than

140/90 mm Hg.

18 Antihypertensives that have been associated with a stroke reduction

risk are the angiotension converting enzyme inhibitor (ACE-I), hydrochlorothiazide,

and calcium-channel blockers.

19 Because she is already receiving lisinopril and her

blood pressure is poorly controlled, it is likely that a combination therapy is needed.

The addition of hydrochlorothiazide 25 mg/day is advisable to R.B.

4

Diabetes is another important risk factor for in RB. In older women, diabetes is a

more significant risk factor for stroke than it is for men.

20 There is controversy

regarding the intensity of glucose control that optimally reduces stroke risk. Clearly,

good control of diabetes results in better control of hypertension and other risk

factors for stroke.

21 Additionally, use of oral hypoglycemics may reduce the risk of

stroke through mechanisms other than glycemic control. However, strict control of

blood glucose did not reduce the risk of stroke over the course of 9 years in one

study.

21 There is evidence that angiotensin-converting enzyme inhibitors (ACEIs) and

angiotensin receptor blockers (ARBs) reduce the risk of stroke in diabetics, with or

without hypertension.

22

,

23 For diabetic patients with at least one additional risk factor

for cardiovascular disease, taking a β-hydroxy-β-methylglutaryl-CoA (HMG-CoA)

reductase inhibitor appears to reduce the risk of stroke by approximately 24% even

in the absence of hypercholesterolemia.

24

,

25

It is known that HMG-CoA reductase

inhibitors have anti-inflammatory activity that may influence the development of

atherosclerotic plaques and cerebral ischemic processes.

26–28 Because of these

effects of HMG-CoA reductase inhibitors, these drugs should be started for primary

prevention of ischemic stroke and TIA even in patients who do not have dyslipidemia

if the estimated 10-year risk of cardiovascular events is high, as recommended in the

2013 “ACC/AHA guideline.”

4

Table 61-2

Primary Prevention of Ischemic Stroke

Factor Goal Recommendation

Hypertension Blood pressure <140/90 mm Hg Follow JNC-8 guidelines; after

lifestyle modification thiazide-type

diuretic, angiotensin-converting

enzyme inhibitor, or angiotensin

receptor blocker, CCB (full

discussion in Chapter 9, Essential

Hypertension)

Atrial fibrillation When warfarin is used, INR 2–3 Aspirin 75–325 mg/day or warfarin,

rivaroxaban, dabigatran, apixaban,

or edoxaban as determined by the

use of the CHADS2

or

CHA2DSC2-VASC score (full

discussion in Chapter 15, Cardiac

Arrhythmias)

Dyslipidemia National Cholesterol Education

Program III goals

Lifestyle modification, HMG-CoA

reductase inhibitor (full discussion in

Chapter 8, Dyslipidemias)

Women (>65 years, history of

hypertension, hyperlipidemia,

diabetes, or 10-year cardiovascular

risk ≥10%)

Reduce risk without bleeding

complications

Aspirin 75–325 mg/day; use the

lowest possible dose

Cigarette smoke Elimination of cigarette smoke Smoking cessation; avoidance of

environmental tobacco smoke

Physical inactivity ≥30 minutes daily of moderateintensity activity

Establish exercise program of

aerobic activity

Excessive alcohol intake Moderation ≤2 drinks/day for men or ≤1

drink/day for nonpregnant women

Diet and nutrition ≤2.3 g/day of sodium; ≥4.7 g/day of

potassium

Institute a diet that is high in fruits

and vegetables and low in saturated

fats

Elevated lipoprotein(a) Reduction of lipoprotein(a) by

≥25%

Niacin 2,000 mg/day as tolerated

HMG-CoA, β-hydroxy-β-methylglutaryl-CoA; INR, international normalized ratio; JNC-8, Eighth Report of the

Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

Source: Meschia JF, et al. Guidelines for the primary prevention of stroke: a statement for healthcare professionals

from the American Heart Association/American Stroke Association. Stroke. 2014;45:3754–3832

p. 1305

p. 1306

Niacin, fibric acid derivatives, ezetimibe, or bile acid sequestrants can be

considered for patients who do not tolerate HMG-CoA reductase inhibitors or have

low high-density lipoprotein cholesterol concentrations; however, their efficacy in

preventing a stroke is not established. The benefits of HMG-CoA reductase

inhibitors appear to be a class effect, so selection of a specific agent should be based

on the individual characteristics of the patient. For R.B., she should maintain tight

control of her diabetes, continue her lisinopril, and start an HMG-CoA reductase

inhibitor, such as simvastatin or atorvastatin.

The body mass index for R.B. is 30.2 kg/m2

, placing her in the obese category.

Multiple large studies have demonstrated a direct relationship between increased

body weight and an increased risk of stroke.

29

,

30 There are no data available to

establish the precise effect of weight reduction on reducing the risk of stroke.

However, increasing physical activity and proper nutrition are essential to achieve

weight loss and improve diabetes and blood pressure control.

31

A diet high in sodium is associated with an increased risk in stroke, whereas a diet

high in potassium appears to reduce the risk of stroke.

32

,

33 Current recommendations

for diet are for sodium intake of 2.3 g/day or less and potassium intake of at least 4.7

g/day.

4

In addition, a DASH-style diet, which emphasizes fruits, vegetables, and lowfat dairy products and reduced saturated fat is recommended to lower blood pressure

and thereby reduce the risk of stroke.

Regarding physical activity, several studies have shown an inverse relationship

between physical activity and risk of stroke.

34

,

35 Therefore, at least 40 minutes/day of

moderate-intensity exercise is recommended three to four times/week.

4 Cigarette

smoking is an independent risk factor for stroke and potentiates other risk factors. In

addition to active smoking, passive inhalation of cigarette smoke also appears to be a

risk factor for stroke.

36 Smoking cessation does result in a rapid reduction in the risk

of stroke, but the risk never returns to levels seen in individuals who have never

smoked.

37

Finally, five studies have specifically investigated the effect of hormone

replacement on stroke risk.

38–42 On the basis of the results from these studies, R.B.

should discontinue her conjugated estrogen/medroxyprogesterone product unless she

is taking this medication for a specific reason other than control of menopausal

symptoms or prevention of cardiovascular events. R.B. should be encouraged to

avoid passive smoke and to continue avoiding the use of tobacco. R.B. should initiate

a weight-reduction program that includes a low-sodium and high-potassium diet with

an exercise program.

Pharmacotherapy Primary Prevention of Ischemic

Stroke and Transient Ischemic Attacks

CASE 61-1, QUESTION 2: Would R.B. benefit from any antiplatelet or anticoagulation for the primary

prevention of ischemic stroke and TIAs?

Aspirin has been carefully investigated for primary prevention of stroke. Although

aspirin is recommended in the primary prevention of coronary heart disease, it is not

generally recommended for the primary prevention of stroke or TIA in low-risk

patients (10-year risk<10%).

4

In high-risk patients (>10-year risk >10%), the use of

aspirin for cardiovascular (including but not specific to stroke) prophylaxis is

reasonable. A patient’s 10-year risk can be calculated using online calculators such

as http://my.americanheart.org/cvriskcalculator.

In a study of 22,071 male physicians who took 325 mg of aspirin or placebo every

other day for 5 years, stroke incidence was similar between groups. In addition, there

was an increased risk of cerebrovascular events caused by hemorrhage in the aspirin

group. Chen et al. reported a meta-analysis of 40,000 patients randomly assigned to

aspirin and found a reduction from 47% to 45.8% in death and disability attributable

to stroke.