Ischemic Stroke

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55 Ischemic Stroke

Ischemic stroke is the third most frequent cause of mortality in the United States and a common cause of prolonged morbidity. Over time it has become more apparent that ischemic stroke represents a constellation of etiologies and mechanisms that often present with similar symptoms and signs. New technology has improved understanding of stroke pathophysiology that promises to translate into more specific treatments and better outcomes.

The distinction between transient ischemic attacks (TIAs) and strokes based on reversibility or not of ischemic symptoms has become less clinically relevant, because a significant number of patients with transient ischemic symptoms have been found to have strokes on diffusion-weighted imaging. Therefore, the diagnostic approach to patients with transient or persistent ischemic symptoms should be the same, and treatment guided toward the underlying cause of the brain ischemia.

Etiology and Pathophysiology

The most common ischemic stroke etiologies are large artery occlusive disease, cardioembolism, and small vessel disease.

Large Artery Occlusive Disease

Atherosclerosis causes stenosis or occlusion of extracranial and intracranial arteries and is directly responsible for a significant percentage of cerebral ischemic events. Atheroma formation involves the progressive deposition of circulating lipids and ultimately fibrous tissue in the subintimal layer of the large and medium arteries, occurring most frequently at branching points (Fig. 55-1). Plaque formation is enhanced by blood-associated inflammatory factors as well as increased shear injury form uncontrolled blood pressure. Intraplaque hemorrhage, subintimal necrosis with ulcer formation, and calcium deposition can cause enlargement of the atherosclerotic plaque with consequent worsening of the degree of arterial narrowing.

Figure 55-1 Atherosclerosis, Thrombosis, and Embolism.

Disruption of the endothelial surface triggers thrombus formation within the arterial lumen through activation of nearby platelets by the subendothelial matrix. When platelets become activated they release thromboxane A₂, causing further platelet aggregation. The development of a fibrin network stabilizes the platelet aggregate, forming a “white thrombus.” In areas of slowed or turbulent flow within or around the plaque the thrombus develops further, enmeshing red blood cells (RBCs) in the platelet–fibrin aggregate to form a “red thrombus” (Fig. 55-2). This remains poorly organized and friable for up to 2 weeks and presents a significant risk of propagation or embolization. Either the white or red thrombus, however, can dislodge and embolize to distal arterial branches. Large artery disease can cause ischemic strokes by either intra-arterial embolism as described above and, less commonly, hemodynamic ischemia or hypoperfusion through a significantly narrowed vessel.

Figure 55-2 Role of Platelets in Arterial Thrombosis.

Frequent sites for carotid system or anterior circulation atherosclerosis are the origin of the internal carotid artery (ICA), the carotid siphon at the base of the brain (Fig. 55-3), and the main stem of the middle cerebral artery (MCA) and the anterior cerebral artery (ACA). The internal carotid artery at or around the bifurcation is usually affected in Caucasians whereas in Asian, Hispanic, and African-American populations, intracranial atherosclerosis may be more common than carotid disease. In the vertebrobasilar system, the origins of the vertebral arteries in the neck and the distal portion of the intracranial vertebral arteries are the most commonly affected areas. The basilar artery and origins of the posterior cerebral arteries (PCAs) are other sites.

Figure 55-3 Common Sites of Cerebrovascular Atherosclerotic Occlusive Disease.

The main risk factors for large artery disease are arterial hypertension, diabetes, hypercholesterolemia, and smoking. Epidemiologic studies have identified hyperhomocysteinemia as a possible risk factor for atherosclerosis, with a twofold greater risk of stroke. However, recent randomized trials have not shown a correlation between moderate reduction of total homocysteine levels and vascular outcomes and theorize it may represent an “innocent bystander” rather than have a direct pathological effect. Further studies are needed to determine if there are subgroups that might benefit from a more aggressive vitamin therapy, particularly over the long term.

Cardiac Embolism

Several types of cardiac disease lead to cerebral embolism: cardiac arrhythmias, ischemic heart disease, valvular disease, dilated cardiomyopathies, atrial septal abnormalities, and intracardiac tumors (Fig. 55-4).

Figure 55-4 Cardiac Embolism.

Cardiac arrhythmias including chronic or paroxysmal atrial fibrillation (AF) and sick sinus syndrome (in particular bradytachycardia syndrome) are the rhythms most associated with cardioembolic event, with stroke often being their first manifestation. Because such arrhythmias are often intermittent, careful and at times repeated monitoring is needed to identify their presence as they pose a significant risk for recurrent stroke.

Within the first 4 weeks of myocardial infarction (MI), particularly with ischemia of the anterior wall, there is a higher risk of embolic stroke. More remote MIs can be a potential embolic source, particularly in patients who develop akinetic segments or left ventricular aneurysms. Mural thrombi are common in patients with dilated cardiomyopathies. Brain embolism is estimated to occur in approximately 15% of these patients.

Rheumatic valvular disease, mechanical prosthetic heart valves, and infective endocarditis are well-known cardiac sources of embolism. Other relatively common abnormalities, mitral valve prolapse, mitral annulus calcification, and bicuspid aortic valve have suspected embolic potential. However, these should be considered as a potential cause of stroke only after other etiologies have been excluded.

Patent foramen ovale (PFO) and atrial septal aneurysm are risk factors for stroke. A meta-analysis of case–control studies comparing patients younger than 55 years with ischemic stroke to nonstroke controls showed an odds ratio for stroke of 3.1 for PFO alone and of 6.1 for PFO with an associated atrial septal aneurysm. Potential or presumed mechanisms of stroke included venous “paradoxical embolism,” direct embolization from thrombi formed within the PFO or atrial septal aneurysm, and thrombus from atrial arrhythmias thought to be more prevalent in this population.

Atrial myxomas, although rare, are important causes of embolic strokes. These tumor emboli frequently affect the vasa vasorum, leading to the development of multiple and peripheral cerebral aneurysms similar to mycotic aneurysms.

Small Vessel Disease (Lacunes)

The capillary vessel and the end penetrating arteries that supply the basal ganglia, thalamus, internal capsule, and white matter tracts are not prone to atherosclerosis as in the large-caliber cerebral circulation but undergo a characteristic pathologic degeneration in response to endothelial damage. Fibrinoid degeneration with focal enlargement of the vessel wall, foam cell invasion of the lumen, and hemorrhagic rupture through the vessel wall characterize this process known as fibrinoid degeneration or lipohyalinosis. Occlusion of these arteries causes small (1–20 mm), discrete, and often irregular lesions called lacunes. As previously alluded to, lacunes do not involve the cortical ribbon and occur most often in the basal ganglia, thalamus, pons, internal capsule, and cerebral white matter and may cause discrete clinical syndromes but often go clinically unnoticed. Arterial hypertension and diabetes are the main risk factors (Fig. 55-5).

Figure 55-5 Lacunar Infarction.

Arterial Dissection

Dissection or tear within the extracranial ICA, particularly its pharyngeal and distal segments, or the extracranial vertebral artery, mainly in its first and third segments, are the two commonly affected vessels. Dissection occurring between the intima and media usually causes stenosis or occlusion of the affected artery, whereas dissection between the media and adventitia is associated with aneurysmal dilatation. Congenital abnormalities in the media or elastica of the arteries as seen in Marfan syndrome, fibromuscular dysplasia, and cystic medial necrosis can predispose patients to arterial dissection. Although often associated with acute trauma, arterial dissection may result from seemingly innocuous incidents, such as a fall while hiking or skiing; sports activities, particularly wrestling or diving into a wave; and paroxysms of coughing. The mechanism of stroke involves clot formation in the dissected wall of the vessel with distal propagation or embolization. Also, expansion of the clot in the dissected wall causes progressive narrowing of the lumen, leading to compromised blood flow and hypoperfusion or, ultimately, occlusion (Fig. 55-6).

Figure 55-6 Arterial dissection.

Less Common Stroke Etiologies

Although frequently considered in the differential diagnosis of ischemic stroke, arteritis is a rare stroke etiology. Usually, CNS vasculitis presents as an encephalopathy with multifocal signs.

Cocaine and amphetamine are the most frequent drugs associated with ischemic strokes. Vasoconstriction and vasculitis are the posited mechanisms.

Hematologic disorders such as polycythemia, sickle cell disease, and thrombocytosis (usually platelets >1,000,000/dL) can cause ischemic strokes by increasing blood viscosity, hypercoagulability, or both. Antithrombin III, protein S, protein C deficiencies, factor V Leiden, and prothrombin gene mutation are usually associated with venous and not arterial thrombosis but may take on importance in cases of stroke associated with PFO due to passage of venous clots through an intra-atrial defect (paradoxical embolization).

Clinical Presentation

Large Artery Occlusive Disease

Carotid Artery Disease

Clinical Vignette

A 68-year-old white man with a history of hypercholesterolemia and 50-pack-year smoking presented with transient episodes affecting the right side of his body. During the first episode, he had weakness of his right leg, lasting for about 10 minutes. The second spell happened 1 week later and was characterized by speech difficulties, right facial drop, and right arm weakness that lasted for 2 hours. The patient came to the emergency department (ED) 3 days later. Brain magnetic resonance imaging (MRI) with diffusion-weighted imaging demonstrated two small strokes in the left frontal lobe, one in the ACA territory and the second one in the MCA distribution. Magnetic resonance angiography (MRA) of the head and neck was remarkable for a 70–80% stenosis of the left ICA, confirmed by carotid ultrasound. The patient was started on antiplatelet treatment and a statin. Smoking cessation education was provided. A right carotid artery endarterectomy was successful, with no subsequent TIAs.

Clinical Vignette

A 70-year-old white man with arterial hypertension and high cholesterol presented with 1 month of recurrent 1- to 2-minute episodes of left extremities shaking that occurred only on standing. His blood pressure (BP) was 110/80 mm Hg, and neurologic examination showed a left pronator drift, but was otherwise normal.

Head computed tomography (CT) showed small strokes in the arterial border zone between the right MCA and ACA and right MCA and PCA distributions. Head and neck computed tomography angiography (CTA) demonstrated a right ICA occlusion. CT perfusion showed hypoperfusion in the right MCA territory, worse in the border zone areas. Collateral flow through the right ophthalmic, anterior communicating, and posterior communicating arteries was detected by transcranial Doppler and conventional angiogram. Patient was started on antiplatelet treatment as well as a statin drug and his antihypertensive medication dose was decreased, with a subsequent increase in the systolic BP to 140–150 mm Hg. No further episodes occurred.

The above vignettes illustrate the two mechanisms of stroke or TIA in large artery atherosclerotic disease, intra-arterial embolism (the first vignette) and hypoperfusion (the second vignette). Identification of the exact mechanism has important therapeutic implications.

TIAs are common in patients with carotid artery disease and usually precede stroke onset by a few days or months. TIAs caused by intra-arterial embolism from a carotid source may not be stereotypical. TIA symptoms vary, depending on which ICA branch is involved. For example, patients can have a first episode of a transient right leg weakness and weeks later have another spell characterized by expressive aphasia, right facial droop and weakness of the right hand. This depends on the destination of the emboli. In the first example, the ACA territory is the destination and in the later example, the MCA territory. In contrast, hemodynamic “limb-shaking” TIAs as in the second vignette presented above are often stereotypical and posturally related and are usually seen in patients with high-grade ICA stenosis or occlusion. In this classic example of a hemodynamic ischemia, patients present with recurrent, irregular, and involuntary movements of the contralateral arm, leg, or both, usually triggered by postural changes and lasting a few minutes. These spells likely represent intermittent loss of cortical control and paralysis and differ from a focal seizure in which the movements are more regular and rhythmic and usually correlate with focal repetitive cortical hyperactivity seen on electroencephalogram.

Another important clue to ICA disease is episodes of transient monocular blindness (TMB). TMB refers to the occurrence of temporary unilateral visual loss or obscuration that is classically described by careful observers as a horizontal or vertical “shade being drawn over one eye,” but most frequently as a “fog” or “blurring” in the eye, lasting 1–5 minutes. It often occurs spontaneously but at times is triggered by position changes. Positive phenomena such as sparkles, lights, or colors evolving over minutes are more typical of migrainous phenomena and help to differentiate such benign visual changes from the more serious TMB, a frequent harbinger of cerebral infarct within the carotid artery vasculature. Rarely, with critical ipsilateral internal carotid stenosis, gradual dimming or loss of vision when exposed to bright light, such as glare of snow on a sunlit background, can be reported and is due to limited vascular flow in the face of increased retinal metabolic demand. Besides carotid atherosclerosis, other etiologies of TMB include cardiac embolism and intrinsic ophthalmic artery disease due to processes such as atherosclerosis or arteritis (see Giant cell or Temporal arteritis in Chapter 11), as well as decreased retinal perfusion from glaucoma or increased intraocular pressure. It is not uncommon that homonymous field deficits are reported by patients as monocular visual loss off to the affected side, and careful questioning as to whether each eye was checked independently and whether the visual difficulty involved the perception of a quadrant or one half of the visual world is essential. For example, patients with left occipital infarctions or transient ischemia may report right-sided vision loss, but further questioning reveals that they were unable to read the right side of street signs or a license plate and while covering the “unaffected” left eye the seemingly abnormal right eye had retained vision within the distribution of the unaffected left homonymous field (Fig. 55-7).

Figure 55-7 Ocular Signs of Large Vessel Disease.

As in the first vignette, strokes from intra-arterial embolism from ICA disease are usually cortically based. Symptoms depend on whether branches of the MCA, ACA, or both are involved. The PCA territory may rarely be affected by intra-arterial emboli from ipsilateral ICA stenosis or occlusion in patients with anomalous normal vascular variants as in a persistent fetal PCA.

Neurologic findings vary by the location of the occlusion and presence of collateral circulation (Fig. 55-8). A large MCA stroke is usually seen in patients with MCA main stem occlusion without good collateral flow, whereas deep or parasylvian strokes are the most common presentation when enough collateral flow is present over the convexities.

Figure 55-8 Occlusion of Middle and Anterior Cerebral Arteries.

Contralateral motor weakness involving the foot more than the thigh and shoulder, with relative sparing of the hand and face is the typical presentation of distal ACA branch occlusion. Conversely, prominent cognitive and behavioral changes associated with contralateral hemiparesis predominate in patients with proximal ACA occlusions and the involvement of the recurrent artery of Huebner (caudate and interior limb of internal capsule infarct).

Hemodynamic strokes usually involve the border zone territory between ACA and MCA (anterior border zone), MCA and PCA (posterior border zone), or between deep and superficial perforators (subcortical border zone) and cause typical clinical symptoms outlined in Table 55-1.

Table 55-1 Clinical Symptoms in Patients with Border Zone Strokes

Stroke Location	Clinical Symptoms
Anterior border zone	Contralateral weakness (proximal > distal limbs and sparing face), transcortical motor aphasia (left-sided infarcts), mood disturbances (right-sided infarcts)
Posterior border zone	Homonymous hemianopsia, lower-quadrant-anopsia, transcortical sensory aphasia (left-sided infarcts), hemineglect, and anosognosia (right-sided infarcts)
Subcortical border zone	Brachiofacial hemiparesis with or without sensory loss, subcortical aphasia (left-sided infarcts)

Intracranial MCA and ACA Disease

Clinical Vignette

A 70-year-old woman with history of diabetes mellitus and hypercholesterolemia presented to the ED reporting mild right-sided weakness first noticed on awakening 2 days previously. The hemiparesis progressed to a right hemiplegia with dysarthria within 48 hours without change in the patient’s level of consciousness. Head CT demonstrated a stroke involving the left centrum semiovale. Head CTA showed a distal M1 segment stenosis. Patient was started on an antiplatelet treatment and a statin. Pharmacologic treatment for her diabetes was maximized. Once stable, patient was transferred to a rehabilitation facility with partial recovery of her motor deficits.

This vignette describes a classic course of subcortical infarct from poor perfusion of the lenticulostriate vessels secondary to a fixed lesion in the ipsilateral MCA. The patient’s symptoms evolved from relatively mild hemiparesis to complete paralysis within 2 days. Unlike large MCA infarctions, there was no impairment of the patient’s level of consciousness despite the progressive nature of the neurologic deficit. In contrast, large cortical MCA lesions may also evolve over 2–4 days but due to development of cerebral edema and increased intracranial pressure, altered level of consciousness and even coma are commonly seen.

Intrinsic occlusive disease of the MCA and ACA are more common in Asians, Hispanics, and African Americans than in Caucasians and are more common in women than in men. Arterial hypertension, diabetes, and smoking are the most common risk factors, with a lower incidence of high cholesterol, coronary artery disease, and peripheral vascular disease. Although TIAs can occur, they are not as common as in patients with ICA disease and usually occur over a shorter period of hours or days. When strokes occur, initial symptoms are typically noticed on awakening and often fluctuate during the day, supporting a hemodynamic mechanism.

Vertebrobasilar Disease

Clinical Vignette

A 76-year-old white man with a history of hypercholesterolemia and a previous myocardial infarction had acute onset of vertigo associated with vomiting and gait difficulties 2 days before presentation. On admission, he had sudden onset of slurred speech and lack of right arm coordination. Head CT demonstrated an old right posterior–inferior cerebellar artery (PICA) stroke and a subacute left PICA stroke. Head MRI with diffusion-weighted imaging showed a new right superior cerebellar artery stroke. Head and neck CTA showed occlusion of the left vertebral artery (VA) origin, a hypoplastic right vertebral artery, and an embolus in the middistal portion of the basilar artery. He was started on a statin and on anticoagulation. Clinically, the patient improved significantly.

The vertebral arteries originate from the subclavian arteries in the neck. Stenosis or occlusion of the proximal subclavian arteries and the vertebral arteries at their origin rarely causes symptoms because of the concomitant development of adequate collateral circulation within the neck through the thyrocervical and costocervical trunks and other subclavian artery branches eventually flowing into the distal vertebral artery (see Fig. 55-3). More often, patients with subclavian and concomitant vertebral-origin stenosis have symptoms related only to upper extremity ischemia. They report pain, coolness, and weakness of the ipsilateral arm. Rarely does chronic atherosclerotic disease at the vertebral origins, even when bilateral, cause significant vertebrobasilar system flow reduction to cause symptoms. When stenosis or occlusion of the VA origin leads to TIAs or stroke, intra-arterial embolism is the commonly recognized mechanism. The embolus usually lodges in the distal vertebral artery, causing a PICA stroke, or passes through, leading to a “top of the basilar syndrome” (Table 55-2).

Table 55-2 Clinical Manifestations of Ischemia in the Vertebrobasilar System According to the Artery Involved *

Involved Artery	Ischemic Manifestations
Vertebral or PICA penetrator arteries (Lateral medullary or Wallenberg syndrome)	Ipsilateral limb ataxia and Horner syndrome, crossed sensory loss, vertigo, dysphagia, hoarseness
PICA	Vertigo, nausea, vomiting, gait ataxia
AICA	Gait and limb ataxia, dysfunction of ipsilateral CN-V, -VII, -VIII
SCA	Dysarthria and limb ataxia
_______________________________________________	______________________________________________________________________________
PCA right	Contralateral visual field cut and sensory loss, visual neglect, prosopagnosia (inability to recognize faces)
Left	Contralateral visual field cut and sensory loss, alexia without agraphia, anomic or transcortical sensory aphasia, impaired memory and visual agnosia
Top of the basilar syndrome	Rostral brainstem–somnolence, vivid hallucinations, dreamlike behavior, and oculomotor dysfunction. Temporal + occipital regions—hemianopsia, fragments of Balint syndrome, agitated behavior, and amnestic dysfunction

* AICA, anterior inferior cerebellar artery; PCA, posterior cerebral artery; PICA, posterior–inferior cerebellar artery; SCA, superior cerebellar artery

Distal intracranial VA atherosclerotic disease most often occurs at the level of the penetrators to the lateral medulla and at the take-off to the PICA. Occlusion at this site presents as a Wallenberg syndrome (lateral medullary syndrome) or cerebellar PICA stroke or both. Lateral medullary syndrome progressing into coma and herniation due to an associated large PICA cerebellar infarction is not uncommon and emphasizes the need to investigate and closely observe those with Wallenberg syndromes for unfolding signs of wider neurologic involvement.

Atherosclerosis of the basilar artery most often affects its proximal and mid portions. Patients experience TIAs characterized by transient diplopia, dizziness, incoordination, and weakness affecting both sides at once or alternating between sides over minutes and even hours or days (Fig. 55-9). As in other occlusive large artery disease, some patients with severe basilar stenosis develop prominent headaches in the weeks before focal symptoms commence. The headache is thought to be from developing posterior circulation collateral flow. When stroke occurs, the most commonly affected area is the basis pons, with bilateral, often asymmetric, hemiparesis, pseudobulbar syndrome, abnormalities of eye movements (sixth nerve palsy, unilateral or bilateral internuclear ophthalmoplegia, ipsilateral conjugate gaze palsy, “one and one-half syndrome”), nystagmus, and if the reticular activating system is involved, coma (Fig. 55-10). Presence of coma or altered level of consciousness is dependent on collateral flow to the tegmentum from other vessels. If the pontine and midbrain tegmentum is spared, bilateral motor and sensory signs as well as varying degrees of ophthalmoplegia may be present without altered consciousness, such as in the “locked in” syndrome.

Figure 55-9 Ischemia in Vertebrobasilar Territory: Clinical Manifestations.

Figure 55-10 Basilar Artery Occlusion.

Embolus to the distal basilar artery leads to the classic top of the basilar syndrome (Fig. 55-11). Affected areas are the rostral brainstem (penetrator branches from distal basilar artery), the thalamus (penetrators of the proximal PCAs), and the medial temporal and occipital lobes. Clinical presentation includes bilateral homonymous hemianopsias or cortical blindness, confusion, vivid-formed visual hallucinations (peduncular hallucinations), and inability to form new memories. In contrast, emboli moving past the basilar tip cause only unilateral PCA occlusions, with isolated homonymous hemianopsias.

Figure 55-11 Occlusion of “Top Basilar” and Posterior Cerebral Arteries.

Most PCA infarcts are either cardioembolic or from intra-arterial embolism. Intrinsic PCA stenosis can occur but is rare. Clinical symptoms consist of transient episodes of hemivisual loss with, at times, associated contralateral sensory symptoms that precede the stroke onset by weeks or days. When headaches occur, they are often retro-orbital or around the brow. In addition to visual and sensory abnormalities, patients with left PCA strokes often have concurrent anomic or transcortical sensory aphasia, impaired memory, associative visual agnosia (recognition) and, when involving the posterior commissure, alexia without agraphia (inability to read with preserved writing). Patients with right PCA stroke often have associated visual neglect and prosopagnosia (difficulty in recognizing familiar faces or specific items of a recognizable group). Bilateral parieto-occipital damage (Balint syndrome) leads to inability to view a grouped visual stimulus as a whole (asimultanagnosia), loss of accurate visual fixation and ocular tracking (optic apraxia), and impaired precision pointing to a visual target (“optic ataxia”). Bilateral occipital cortex injuries produce an inability to recognize all visual stimuli, often with absent insight into the deficit (cortical blindness or Anton syndrome).

Cardioembolic Disease

Clinical Vignette

A 59-year-old physician suddenly had difficulty driving; his wife noted that their car almost hit objects off to the right side. When questioned, he agreed that he was having difficulty seeing to the right. When this did not improve overnight, he was evaluated in the ED, revealing a dense right homonymous hemianopsia. Otherwise, neurologic and general physical examination were normal. Brain CT demonstrated a left occipital lobe hypodensity compatible with PCA infarction. MRI confirmed these findings, and MRA revealed a left PCA origin occlusion. A 48-hour Holter monitor demonstrated paroxysmal AF. Warfarin sodium was administered with careful monitoring. His right homonymous hemianopsia did not improve and he was told not to drive. Otherwise, he successfully compensated for this loss of vision.

Atrial fibrillation, paroxysmal or chronic, is one of the most common sources of cardiac brain embolism and accounts for up to 15–20% of all ischemic stroke. The incidence of atrial fibrillation in the population older than age 65 years is estimated at around 6%, but most patients do not experience embolic events. Risk factors that predispose to stroke or embolization from nonvalvular atrial fibrillation include age older than 75 years, hypertension, ejection fraction below 35%, and congestive heart failure. Conditions such as coronary artery disease, thyrotoxicosis, and female gender may represent other factors that play a lesser role. Multiple risk factor increase the likelihood of major stroke up to sevenfold and should be strongly considered for antithrombotic treatment. Those who present with TIA or stroke hold the highest risk or recurrence around 12% a year for the first year, then 5–6% yearly thereafter. Atrial flutter, although a more organized cardiac arrhythmia, still predisposes to emboli formation and should be approached in the same fashion as atrial fibrillation.

Strokes secondary to cardiac sources typically present with acute onset of focal neurologic deficits, such as sudden loss of hand control or drooping of the mouth, often associated with language dysfunction, if involving the dominant hemisphere, or neglect if involving the nondominant hemisphere. Cerebral emboli are most clinically apparent during the day, and patients often provide a precise time of stroke or TIA onset. Cardioembolic stroke typically occurs during the waking hours with patient activity, in contrast to intra-arterial thrombosis or artery-to-artery embolism that often occur in sleep when rheological factors may favor increased coagulation. The anterior carotid circulation receives 80% of cerebral blood flow and is four times more likely than the posterior vertebrobasilar circulation to be affected with emboli. Furthermore, a history of TIAs, strokes, or both, affecting both carotid and vertebrobasilar territories increases the suspicion of cardiac embolism. The vessels more often affected by cardiac emboli are the MCA and its branches, followed by the distal portion of the intracranial vertebral artery, distal basilar (top of the basilar syndrome), and the PCA territory.

Emboli from recent MI typically are more likely to occur within the first 2 weeks of the acute event. Patients with anterior wall myocardial infarctions may develop segmental hypokinetic myocardial wall defects or even aneurysms. Such lesions provide a potential nidus for platelet aggregation with subsequent embolus formation.

Infective endocarditis presents with TIA or stroke in approximately 15% of cases, but eventually 30% of patients are likely to experience a major neurologic complication throughout the course of the illness. Individuals with valvular heart disease are particularly at risk for developing endocarditis after any procedure that leads to transient bacteremia, even those as innocuous as dental cleaning, and should be treated beforehand with prophylactic antibiotics. Intravenously illicit drug use is also a major risk for infective endocarditis because of the reuse of nonsterilized needles. Endocarditis commonly presents with systemic symptoms, such as fever, weight loss, and malaise as well as signs of a new-onset or changing cardiac murmur, petechial rash, microemboli to the nail beds (splinter hemorrhages) and conjunctiva, tender nodules or erythematous lesions in the palms and finger pads (Osler nodes and Janeway lesions), and retinal emboli with exudate (Roth spots). Microemboli affecting the brain diffusely often present as an encephalopathy rather than with focal neurologic findings and may be hard to diagnose in the setting of chronic medical illness.

Clinical Vignette

A previously healthy 41-year-old woman had a right facial droop and difficulty speaking 1 day after she had made a continuous 10-hour car trip. At the ED, neurologic examination confirmed right central facial weakness and a mild mixed expressive and receptive aphasia. Cardiac examination and an electrocardiograph were normal. Brain MRI with diffusion-weighted imaging showed a small left insular stroke. Head and neck MRA results were normal. Transesophageal echocardiography (TEE) showed a patent foramen ovale (PFO), and her hypercoagulable screen was remarkable for protein S deficiency. Symptoms gradually improved, clearing completely within 72 hours.

Despite a clinically normal initial cardiac examination, the TEE confirmed a congenital intra-atrial heart defect. The symptom complex acuity was consistent with a cardioembolic source, justifying a careful heart evaluation. In patients of this age group, PFO is the most likely associated condition with embolic stroke.

Patent foramen ovale and, less encountered atrial septal defects, are common and occur in up to one fourth of the population and usually do not cause cardiac symptoms. This intra-arterial connection is a remnant of the intrauterine fetal circulation that allows placental oxygenated blood to bypass the fetal unaerated lung vasculature directly to the left atrium and fetal systemic circulation. This conduit, which usually closes within a few months of birth, remains partially patent in a large proportion of the population. Any venue that predisposes to increased right-sided pulmonary and right atrial pressures (squatting, straining, lifting, coughing, etc.) would have the theoretical potential of transiently reversing the usual left-to-right intra-atrial gradient, and prompt venous clots that are normally dissolved or filtered in the pulmonary circulation, to cross directly into the left atrium and subsequently the cerebral and systemic arterial circulation. Another presumed mechanism is turbulent or stagnant flow in and around the defect itself, with subsequent clot formation and propagation. PFOs are usually detected by Doppler echocardiography. After a brief delay, intravenous agitated saline or colloid injections are seen as echo-dense air bubbles crossing the intra-atrial septum from right to left. This is often aided by a Valsalva maneuver that transiently increases right-sided atrial pressure with respect to the left. Transesophageal echocardiography holds a higher sensitivity as compared to a transthoracic approach and is considered the test of choice. PFO has been shown to be more common in young adults with cryptogenic stroke as compared to the general population and as compared to those with identifiable sources of stroke. Being a common finding, the presence of a PFO as a cause of paradoxical embolism in cryptogenic stroke remains however presumptive, and other situational, hematologic, and anatomic factors likely come into play that make the PFO clinically relevant. For example, a paradoxical embolism becomes more suspicious in a young patient with a prior history of deep venous thrombosis who presents with a stroke after a bout of coughing from an upper respiratory tract infection during a period of relative immobility. As illustrated in the vignette, patients at risk include those who are nonambulatory from prolonged illness or even seemingly inconsequential settings, such as during prolonged transoceanic flights or car trips where venous flow in the legs is diminished or stagnant. Those with coagulation disorders, either hereditary or acquired such as with hormone replacement therapy or pregnancy, are also at a higher risk. Studies show that the incidence of an associated hypercoagulable hematologic abnormality is higher in patients with cryptogenic stroke and PFO than the general population. Coagulation studies and a search for deep vein thrombosis should be included in the workup for all young patients with cryptogenic stroke and an associated PFO. Anatomic considerations also come into play. A PFO with an associated atrial septal aneurysm (>10 mm protrusion into either atrium) holds a much higher risk of recurrence of up to 19.2% over 4 years even when treated with antiplatelets. A large-size PFO (>1 cm) with many microbubbles crossing the intra-arterial septum, especially without the aid of a Valsalva maneuver, likely represents a high risk of recurrence.

Lacunar Small Vessel Disease

Clinical Vignette

A 71-year-old woman with poorly controlled arterial hypertension developed subacute-onset, initially stuttering, left hemiparesis over 48 hours. She presented 2 weeks later when she had not fully recovered. There was no history of headache, sensory loss, visual changes, or language dysfunction. Neurologic examination demonstrated a pure motor hemiparesis, brisk right-sided muscle stretch reflexes, and a right Babinski sign.

Brain MRI showed a lacuna within the right pons. MRA of the head and neck were normal. The patient was started on antiplatelet treatment and gradually improved during a 2-week stay at the rehabilitation unit, but remained with a slight tendency to circumduct the leg while walking, even 6 months later.

Lacunar strokes affecting the internal capsule, thalamus, striatum, or brainstem (see Fig. 55-5) can often be clinically distinguished from embolic disease by the tendency toward a more insidious onset, with deficits progressing or stuttering on over 2–4 days. Additionally, lacunar deficits have a relatively typical distribution; they affect the entire side of the body with motor and/or sensory symptoms without cortically based findings or visual changes. This is in contrast to middle cerebral artery cortical branch occlusions that tend to have a brachiofacial distribution often associated with other cognitive and/or visual signs.

Patients experiencing lacunar strokes can present with TIA in up to 15–20% of instances. TIAs are stereotypical, and tend to cluster over 2–5 days, at times occurring frequently over a 24-hour period and in a crescendo fashion. Signs and symptoms vary according to the location of the ischemia (Table 55-3).

Table 55-3 Most Frequent Lacunar Syndromes and Their Locations

Clinical Syndrome	Location
Pure motor stroke: weakness equally involving face, arm, and leg	Internal capsule (posterior limb) or basis pontis
Pure sensory stroke: numbness or paresthesia equally involving face, arm, leg and usually trunk	Lateral thalamus (posteroventral nucleus)
Ataxic hemiparesis: weakness and incoordination in the arm and/or leg	Basis pontis or internal capsule
Dysarthria—clumsy hand: facial weakness, severe dysarthria and dysphagia, slight weakness, and clumsiness of the hand	Basis pontis
Rare sensorimotor stroke: combination of pure motor/pure sensory symptoms and findings	Thalamus internal capsule

Hypertension and diabetes are the most important risk factors, and proper treatment of these conditions is essential to prevent further strokes.

Arterial Dissection

Clinical Vignette

A 42-year-old man with no vascular risk factors presented with acute-onset left-sided weakness and numbness. Symptoms were preceded by severe nonspecific right-sided neck and retro-orbital pain for 1 week after he had had a relatively inconsequential fall. Examination revealed evidence of a spastic left hemiparesis and hemineglect of the left arm more than the leg. Head CT showed a complete right MCA stroke, and CTA showed tapering of the right ICA 2 cm above the bifurcation, suggestive of arterial dissection. Patient was treated with heparin and subsequently with warfarin. Repeated CTA 6 months later showed complete recanalization of the right ICA. Warfarin was discontinued and the patient was placed on antiplatelet treatment.

Extracranial carotid artery dissection occurs predominantly in patients aged 20–50 years. The characteristic clinical presentation is unilateral neck or face pain followed a few days later by acute onset of neurologic signs. In patients with carotid dissection, pain is usually referred to the eye, temple, or forehead. Ipsilateral Horner syndrome occurs in 40–50% of patients and is due to distension or pressure against the oculosympathetic fibers running along the internal carotid artery to the eye. Pulsatile tinnitus is common. Often, a history of minor trauma exists (violent coughing, cervical manipulation, whiplash injury, etc.) in the days preceding symptom onset. As in the preceding vignette, benign traumatic events can cause a slight intima tear in the carotid or vertebral arteries, leading to platelet fibrin aggregation with potential for developing artery-to-artery emboli.

TIAs are more common in ICA than on VA dissections. In ICA dissection, TIAs usually involve the ipsilateral eye and cerebral hemisphere. Symptoms of VA dissection are of dizziness, diplopia, gait unsteadiness, and dysarthria. In extracranial ICA and VA dissections, strokes usually affect the MCA and distal VA territories (PICA and lateral medullary). The mechanism of stroke relates to artery-to-artery embolization from clot accumulation and eventual rupture through the media into the vessel lumen. Also progressive true lumen narrowing with hypoperfusion occurs as does eventual occlusion, often following a flurry of successive TIA before the final stroke.

Diagnostic Approach

For every patient evaluated with ischemic stroke or TIA, the location of the lesion and mechanism should be investigated thoroughly to better predict potential complications and to most effectively direct treatment. CT and MRI brain scanning have greatly enhanced our ability to diagnose and follow neurologic disease as well as guide treatment. Noninvasive arterial imaging with CTA and MRA have largely replaced catheter angiography in the initial evaluation of cerebrovascular disease and show great promise in advancing acute stroke care (Fig. 55-12).

Figure 55-12 Intracranial Arterial Imaging with CT and MRI.

Anatomic Site

Although the precise anatomic location of an acute TIA or stroke can frequently be deduced by the history and neurologic examination, confirmation with an imaging study is needed and often provides more specific etiologic information that can direct potential treatment. In addition, intracerebral hemorrhages, subdural hematomas, or other structural lesions including benign and malignant tumors are occasionally found on brain CT and MRI in patients presenting with seemingly typical cerebrovascular events.

Brain CT examination, with its immediate availability in most hospitals and short scanning time, is usually the initial study performed in individuals presenting with an acute focal neurologic deficit. Its sensitivity to detect the presence of a primary cerebral hemorrhage or a hemorrhagic infarct is a crucial starting point in determining the future course of action such as the use of thrombolytics, the need for surgical intervention, and the degree of blood pressure control. The head CT is often normal in the first few hours of an ischemic stroke. However, in some cases, the presence of an acute arterial occlusion can be detected by the presence of a localized intraluminal hyperdense signal, often seen in patients with MCA occlusion (Fig. 55-13A), even when the brain parenchyma shows no evolving processes. Head CT may also show early infarct changes characterized by sulcal effacement or loss of gray–white matter differentiation (Fig. 55-13B). Such findings have important therapeutic implications. A CT angiogram can confirm the presence of a thrombus (Fig. 55-13C) and help guide further intervention concerning intravenous or intra-arterial tissue plasminogen activator (t-PA), anticoagulation, and management of blood pressure.

Figure 55-13 Acute Ischemic Infarct with a Right Middle Cerebral Artery Clot.

Diffusion-weighted MRI is the most sensitive and specific test for acute ischemia, and abnormalities have been demonstrated as early as 1 hour after symptom onset. Combined with concomitant perfusion scanning information, the ischemic penumbra (area of brain with compromised cerebral perfusion but without established infarction) can be defined, and decision concerning the risk and feasibility of reperfusion intervention can now be made more effectively and safely. Other MRI sequences, such as FLAIR and T2-weighted imaging, can show the area of stroke, often 6–12 hours after onset of symptoms (Fig. 55-13D and E).

Etiologic Mechanism

To define the specific pathophysiologic mechanism for a TIA or stroke, patency of the extracranial and intracranial arteries, the character of their endothelial surface, and the adequacy of cerebral perfusion are required.

Complete assessment of cardiac function is essential and includes the electrical stability of the cardiac rhythm, myocardial contractility, valvular status, and whether a PFO is present. TEE provides more sensitivity and anatomic details and is preferred over the transthoracic approach for valvular lesions, intra-atrial abnormalities (PFO and ASD), and aortic arch disease. Ultrasound of the carotid arteries at their bifurcation in the neck and transcranial Doppler of the intracranial vessels can functionally assess cerebral flow and determine the presence of critically stenotic extracranial or circle of Willis arteries, respectively. Carotid ultrasound helps characterize the carotid plaque as “soft” consisting of cholesterol deposits and clot, which is more prone to ulceration and artery-to-artery embolization, or “hard” where the vessel wall has fibrosed and calcified over time, making it a less likely source of distal embolization. MRA or CTA of the head and neck is appropriate to assess patency of intracranial and extracranial arteries. The more recent addition of perfusion scanning helps define the effect of any stenotic lesion upon regional blood flow (Table 55-4).

Table 55-4 Comparison of Neurologic Imaging Techniques *

Imaging Method	Advantages	Disadvantages
MRI/MRA	DWI and PWI demonstrate the area of stroke and the area at risk (penumbra), respectively.	Prolonged test (30–60 min); patient must cooperate or sedation is required. Cannot be performed in patients with PCM. MRA can overestimate tight stenosis as an occluded vessel.
CTA/CTP	Images can be obtained rapidly (<5 min).	Patient must have normal renal function because CTA and CTP require high doses of contrast, 100 and 50 mL, respectively.
Ultrasonography of the neck	Easy to perform, can be done at the bedside	No detailed information about the vertebral arteries or the intracranial vessels.
TCD	Easy to perform, even at the bedside	Poor transtemporal windows limit the information about the intracranial vessels.

* CTA, computed tomography angiography; CTP, computed tomography perfusion; DWI, diffusion-weighted imaging; PCM, pacemaker; PWI, perfusion-weighted imaging; TCD, transcranial Doppler

Information gathered from imaging studies allows differentiation of three primary carotid or vertebrobasilar stroke mechanisms: large artery disease with intra-arterial embolism, small vessel disease, and large artery disease with hemodynamic ischemia.

Renal failure or pacemaker devices limit the imaging studies that can be performed in patients with TIAs and strokes (Table 55-5). Gadolinium-based contrast agents have recently been linked to the development of nephrogenic systemic fibrosis and nephrogenic fibrosing dermopathy, often with serious and irreversible skin or organ pathology in patients with moderate to end-stage renal disease. The mechanism is unclear but thought to be due to stimulation of tissue fibrosis similar to that seen in scleroderma or eosinophilia-myalgia syndrome.

Table 55-5 Guidelines for Imaging in Ischemic Stroke/TIA Apropos Patient Renal Function and Pacemaker Presence *

Normal Renal Function	Presence of PCM	Abnormal Renal Function
CT of the head, CT perfusion, and CTA of head and neck	CT of the head, CT perfusion, and CTA of head and neck	CT of the head, TCD and US
or	or	or
MRI of the head + DWI/PWI, MRA of the head and neck or	CT of the head, TCD and US	MRI of the head MRA of head and neck without use of contrast
CT of the head, TCD and US

* CTA, computed tomography angiography; DWI, diffusion-weighted imaging; PCM, pacemaker; PWI, perfusion-weighted imaging; TCD, transcranial Doppler; US, ultrasonography

A hypercoagulable screen, including protein C, protein S, antiphospholipid antibodies (anticardiolipin antibodies and lupus anticoagulant), factor II DNA, factor V Leiden or protein C resistance, antithrombin III, and homocysteinemia are part of the evaluation of patients younger than 50 years and in patients of any age without identifiable risk factors. It should be kept in mind that most inherited coagulopathies are more associated with systemic and cerebral venous thrombosis rather than arterial stroke and a direct relation cannot be made. Other factors such as smoking, hormonal therapy, and the presence of a PFO may make them more relevant in cases of ischemic stroke without any other clear source.

Treatment

The treatment of ischemic TIAs and strokes can be divided into identification and treatment of vascular risk factors, primary and secondary stroke prevention, treatment of the acute phase of stroke, surgical treatment and rehabilitation.

Identification and Treatment of Vascular Risk Factors

Well-documented and modifiable risk factors for strokes, such as hypertension and diabetes, should be regularly screened in all patients with or without history of prior TIAs and strokes and appropriately treated according to the 2006 American Heart Association/American Stroke Association (AHA/ASA) guidelines, which include dietary changes, increased physical activity, and pharmacologic treatment.

Statins have been approved for prevention of ischemic strokes or TIAs in patients with elevated cholesterol, comorbid coronary artery disease, or evidence of an atherosclerotic origin. Treatment should aim for a target low-density lipoprotein cholesterol (LDL-C) level of <100 mg/dL and for high-risk patients with multiple risk factors an LDL-C <70 mg/dL is usually recommended.

Since the publication of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, statins have been recommended for patients with atherosclerotic ischemic stroke or TIA even without known coronary heart disease to reduce the risk of both subsequent stroke and cardiovascular events. This trial showed a 5-year absolute risk reduction of 2.2% for the combination fatal and nonfatal stroke and of 3.5% absolute risk reduction for major cardiovascular events in patients receiving 80 mg of atorvastatin as compared with placebo. The two treatment groups have no significant differences in the incidence of serious adverse events; however, there were slightly more hemorrhagic strokes in the atorvastatin group as compared with placebo (55 vs. 33). Hemorrhagic strokes were more frequent in men, older patients, with hemorrhagic stroke as an entry event, and in patients with stage 2 hypertension (systolic BP ≥ 160 mm Hg, diastolic BP ≥ 100 mm Hg) at the last visit just prior to the hemorrhagic stroke. There was no relationship between the hemorrhagic risk and the LDL cholesterol levels.

Smoking cessation is recommended, and avoidance of environmental tobacco smoke for stroke prevention should be considered in all patients.

Primary and Secondary Stroke Prevention

Primary Prevention

Aspirin is the only antiplatelet agent that has been studied for primary stroke prevention. Five trials have examined the effects of daily or every-other-day aspirin for the primary prevention of cardiovascular events over periods of 4–7 years. Most participants were men older than 50 years. Meta-analysis from these studies showed that aspirin therapy reduced the risk of CHD by 28% but without any significant effect on total mortality and stroke. Most of the data for primary prevention in women comes from The Women’s Health Study. This study showed a nonsignificant reduction for a first major vascular event (nonfatal MI, nonfatal stroke, or cardiovascular death) in women older than age 45 years treated with low-dose aspirin as compared with placebo but a 17% reduction in the stroke risk. The most consistent benefit was for women aged 65 years or older at study entry, among whom the risk of major cardiovascular event or stroke was reduced by 26%, including a 30% reduction of risk of ischemic stroke. Analysis of the subgroups showed a reduction in stroke for those women with history of hypertension, diabetes, hyperlipidemia, or a 10-year cardiovascular risk equal to or greater than 10. Based on the above data, the 2006 guideline update from the AHA/ASA for primary prevention of ischemic stroke recommends the use of low-dose aspirin for cardiovascular prophylaxis among patients whose risk is sufficiently high.

Anticoagulation with warfarin is indicated for primary stroke prevention in patients with atrial fibrillation who have valvular heart disease, particularly mechanical valve. For patients with nonvalvular AFIB, stratification according to stroke risk following CHADS2 (congestive heart failure, hypertension, age >75 years, diabetes mellitus, and prior strokes and TIAs) is recommended. The score gives 1 point for each risk factor and 2 points for strokes and TIAs. Nonvalvular atrial fibrillation patients with CHADS2 score of 0–1 have an annual stroke risk of approximately 1%, and aspirin treatment only is recommended. For patients with a CHADS2 score of 2 (2.5% annual stroke risk) and CHADS2 equal to or greater than 3 (annual stroke risk >4%), anticoagulation is recommended in the absence of contraindications. It is generally recommended that the target international normalized ratio be in the range of 2.0–3.0. Monitored closely within this range, warfarin is generally found to be safe and effective although there continues to be a higher rate of major bleeding complications compared to aspirin. Aspirin treatment alone holds modest benefit for stroke prevention in atrial fibrillation and should be considered in patients who cannot take warfarin.

Secondary Prevention

The benefit of antiplatelets for secondary prevention in patients with a prior history of noncardioembolic stroke or TIA, more specifically, atherosclerotic, lacunar, or cryptogenic stroke, is well established. The most common antiplatelet agents used are aspirin, clopidogrel, and a combination of dipyridamole and low-dose aspirin.

Aspirin is the oldest antiplatelet drug and probably the most often prescribed drug worldwide. It inhibits the cyclooxygenase enzyme preventing production of thromboxane A₂, a stimulator of platelet aggregation. A meta-analysis published in 2002 by the Antithrombotic Trialist’s Collaboration supports the benefits of aspirin for prevention of ischemic stroke and cardiovascular events. This meta-analysis showed that patients at high risk for cardiovascular disease treated with antiplatelets (primarily aspirin) have a 25% relative risk reduction in nonfatal stroke as compared with placebo. The dose of aspirin for secondary stroke prevention varies from 20 to 1300 mg in the different trials. However, most studies have found that 50–325 mg of aspirin a day is as effective as higher doses, with less bleeding complications.

Clopidogrel is a thienopyridine that inhibits ADP-dependent platelet aggregation. In the CAPRIE trial (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events), patients with recent stroke, MI, or peripheral vascular disease were randomly assigned to 75 mg/day of clopidogrel or 325 mg/day of aspirin. The primary end point (composite outcome of stroke, MI, or vascular death) was significantly reduced with clopidogrel as compared with aspirin, with a relative risk reduction of 8.7%. Of note, most of the benefit in this trial was observed in the subgroup of patients with peripheral vascular disease. Clopidogrel had a favorable side effect profile as compared with aspirin, with a slightly lower frequency if GI bleeding and slightly higher frequency of rash and diarrhea.

Despite its proven benefits on stroke prevention, ticlopidine, another thienopyridine, is rarely used because of its potentially serious side effects of severe neutropenia and thrombotic thrombocytopenic purpura (TTP).

Dipyridamole inhibits platelet aggregation induced by the phosphodiesterase. The combination of low-dose aspirin (50 mg) and sustained-release dipyridamole (400 mg/day) for secondary stroke prevention has been shown to be more effective than either drug alone. The relative risk reduction of stroke compared to placebo in the European Stroke Prevention Study (ESPS-2) was 37% for the combination between aspirin and dipyridamole, 18.1% for aspirin, and 16.3% for dipyridamole. Similar benefits were later reported in the European/Australasian Stroke Prevention in Reversible Ischemia Trial (ESPRIT).

Interestingly, the combination of aspirin and clopidogrel for stroke prevention does not show any benefit over treatment with clopidogrel alone (MATCH [Management of Atherothrombosis with Clopidogrel in High-risk patients] trial) or aspirin alone (CHARISMA [Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance] trial), and has a significantly increased risk of life-threatening bleeding complications. Therefore, the combination of clopidogrel and aspirin is not recommended for stroke prevention at this time.

The recent results of the Prevention Regimen for Effectively Avoiding Second Strokes trial (PROGRESS trial) comparing clopidogrel with the combination of aspirin and dipyridamole in more than 20,000 patients with recent atherothrombotic ischemic stroke showed no statistical difference between the groups in the primary outcome of recurrent stroke. Also, the main secondary composite endpoint of stroke, myocardial infarction or vascular death, was similar between the two treatment groups.

Warfarin inhibits vitamin K–dependent coagulation factor synthesis (II, VII, IX, X, proteins C and S). Warfarin has a significant benefit compared with placebo for secondary stroke prevention in patients with AF with an annual stroke rate of 4% in patients receiving warfarin compared with 12% in patients receiving placebo.

According to the WARSS trial, warfarin was not superior to aspirin for prevention of recurrent ischemic strokes or death in patients with a prior noncardioembolic ischemic strokes. Most patients in this trial had small vessel disease (56%) or stroke of unclear etiology (26.1%). Warfarin also showed no advantage over aspirin for prevention of ischemic stroke or vascular death in patients with symptomatic intracranial artery stenosis (WASID trial) and was associated with significantly higher rates of adverse events.

The best treatment for stroke prevention in patients with extracranial dissections remains unclear. The 2006 AHA/ASA guidelines recommend the use of either warfarin or antiplatelets for 3–6 months in patients with extracranial vessel dissections. Beyond 3–6 months, long-term antiplatelet is reasonable for most patients, but anticoagulation may be considered for those with recurrent ischemic events.

For patients with ischemic strokes or TIAs and a PFO, antiplatelet therapy is reasonable to prevent recurrent events. However, warfarin may be preferable for patients with an underlying hypercoagulable state and for those with anatomic features associated with higher recurrence rates such as large PFOs with a vigorous and spontaneous right-to-left atrial shunting and those associated with atrial septal aneurysms. Currently, there is insufficient evidence to support PFO closure in patients with a first-time cryptogenic stroke, and randomized trials comparing the effectiveness of PFO closure versus conventional medical treatment in preventing stroke recurrence are ongoing.

Treatment of the Acute Phase

Acute treatment of patients with ischemic stroke includes general measures, thrombolysis in selected patients, and antiplatelet treatment in patients not treated with thrombolytics.

Deep venous thrombosis prophylaxis, monitoring and control of BP and blood sugars, aggressive treatment of hyperthermia and any associated infection, strict fluid management, and aspiration precautions are basic, but important measures in the first few days of acute stroke.

Despite the high prevalence of arterial hypertension following a stroke, its optimal management has not been well established. High levels of blood pressure in the acute setting of a stroke can increase the risk of hemorrhagic transformation, cerebral edema, and further vascular damage. However, aggressive treatment of the blood pressure can reduce cerebral blood flow in the area of ischemia, increasing the infarct size. The Stroke Council of the AHA recommends for patients not eligible for thrombolytic treatment to withhold treatment with antihypertensive agents unless the diastolic blood pressure is >120 mm Hg or systolic blood pressure is >220 mm Hg. For thrombolytic-eligible patients, systolic blood pressure should be maintained below 180 mm Hg and diastolic below 105 mm Hg during and up to 24 hours after the treatment in order to prevent parenchymal hemorrhage. Intravenous beta blockers and calcium channel blockers such as labetalol and nicardipine, respectively, are first-line agents to control blood pressure levels in those patients. For patients with diastolic blood pressure higher than 140 mm Hg, sodium nitroprusside is the drug of choice.

A randomized double-blind trial of IV recombinant tissue plasminogen activator (rt-PA) in patients with ischemic stroke treated within the first 3 hours of symptom onset showed a 12% absolute (32% relative) increase in the number of patients with minimal or no disability at 3 months in the rt-PA group. The benefit was present for all the different stroke subtypes analyzed. Similar benefits of early treatment with rt-PA within a 3-hour window were also shown in a subpopulation analysis of patients in the ATLANTIS (Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke) trial. This treatment, since approved by the Food and Drug Administration (FDA), has become the standard of care for acute ischemic stroke, and all patients arriving to the hospital within the first 3 hours of symptom onset should be considered for IV rt-PA administration after appropriately screening for thrombolytic contraindications (Box 55-1).

Box 55-1 Contraindications for IV rt-PA *

Relative Contraindications

1. Seizure at onset of stroke

2. Serum glucose <50 mg/dL or >400 mg/dL

3. Hemorrhagic eye disorder

4. Myocardial infarction in the previous 6 weeks

5. Suspected septic embolism

6. Infective endocarditis

7. INR >1.7

^* INR, international normalized ratio; PTT, partial thromboplastin time; rt-PA, recombinant tissue plasminogen activator

In contrast to studies of patients treated within the 3-hour window, most clinical trials of intravenous t-PA in unselected patients presenting after 3 hours of symptoms onset have not shown any clear benefit. However, recent studies using MRI screening criteria have shown a favorable outcome in patients with a baseline diffusion and perfusion mismatch. In theory, the region of hypoperfused but potentially viable brain around an irreversibly damaged area of tissue, may respond favorably to thrombolytic therapy beyond the typical 3-hour window provided the infarcted core is small. The EPITHET trial (Echoplanar Imaging Thrombolytic Evaluation Trial) that evaluated IV t-PA versus placebo in the 3–6-hour window in patients evaluated with advanced neuroimaging showed increased perfusion and a trend toward reduced infarct size in threatened tissue but did not translate into an across-the-board clinical benefit. The ECASS III (European Cooperative in Acute Stroke Study) IV t-PA trial, however, excluded patients at high risk of bleeding and large deficits and supports extending the thrombolytic window to 4.5 hours in patients younger than 80 years with moderate stroke severity who are not taking warfarin or other anticoagulants.

Ultrasound-enhanced intravenous thrombolysis is a promising treatment, but so far remains to have a proven advantage and further study is needed regarding its safety and effectiveness.

Patients with large artery occlusions and severe strokes show only a limited response to intravenous thrombolytics and considerably higher rates of intracerebral hemorrhage. Intra-arterial thrombolysis holds promise in improving the outcomes of these patients, and studies show a recanalization rate of major cerebral vessel occlusions of 50% as compared to around only 25% with intravenous therapy alone. A review of the available data on intra-arterial thrombolysis shows a possible reduction of mortality and more favorable outcomes with this type of therapy, though with an increased risk of hemorrhagic complications as compared to standard intravenous therapy, especially when higher doses of heparin are used during the angiographic procedure. Overall, although promising, there is currently no evidence that intra-arterial thrombolysis is better than intravenous treatment, and IV therapy should not be withheld from eligible patients except in the setting of a comparative trial. Intra-arterial t-PA can, however, be considered in patients who do not qualify for IV t-PA and for those with major intracranial vessel occlusion (basilar artery or mainstem MCA syndromes) outside the 3-hour window but within 6 hours.

The combination of IV and IA thrombolysis has been studied and is based on the idea of uniting the advantages of both treatments: early intervention with IV thrombolysis and higher rates of recanalization with the use of intra-arterial therapy. Earlier trials show a better recanalization rate but with no improvement in clinical outcome when compared with intra-arterial treatment alone. Recent studies (Interventional Management of Stroke Study [IMS]) showed a 56% rate of recanalization in patients treated with the combination; however, similar outcomes and rate of symptomatic hemorrhage are seen as in the NINDS (National Institute for Neurological Disorders and Stroke) IV t-PA treatment group. Further studies are necessary to assess safety and efficacy of combined IA and IV thrombolysis.

Mechanical clot disruption and endovascular embolectomy have been used in the acute treatment of ischemic stroke, with or without intra-arterial thrombolysis. The MERCI (Mechanical Embolus Removal in Cerebral Ischemia) device, a corkscrew-like coil that retrieves the thrombus, is approved by the FDA for clot removal in selected patients. Even though the MERCI trial showed a higher rate of recanalization, there was no evidence of better outcome at 90 days as compared with historical controls from the Prourokinase for Acute Ischemic Stroke II study (PROACT II) Study. The risk of symptomatic intracranial hemorrhage (8%) was similar to that with IV t-PA in the NINDS trial (6.4%).

In patients that are ineligible for thrombolysis, treatment with heparin, low-molecular-weight heparin and aspirin may be considered. Aspirin (160 mg or 325 mg daily) is the only antiplatelet agent that has shown a small but statistically significant reduction in risk of early recurrent ischemic stroke, death and disability when given within 48 hours after ischemic stroke, regardless of the stroke subtype.

Abciximab, unfractionated heparin, LMW heparins, and heparinoids have not been shown to reduce rate of stroke recurrence, mortality, or stroke-related mortality when used within the first 48 hours of stroke onset. Regarding stroke subtype, the TOAST (Trial of ORG 10172 in Acute Stroke) trial showed a possible benefit of IV danaparoid in patients with large artery disease; however, this observation requires prospective validation before it can be given any weight.

Surgical Treatment

Carotid endarterectomy (CEA) for prevention of ischemic stroke has been performed since the early1950s, but it was only in the 1990s that several large-scale trials were performed comparing this type of surgery against best medical treatment in patients with internal carotid artery stenosis.

For the symptomatic patients, evidence from the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the European Carotid Surgery Trial (ECST) support CEA for severe (70–99%) symptomatic stenosis over best medical treatment, with a 17% absolute risk reduction and a 65% relative risk reduction of ipsilateral stroke at 2 years. CEA was not indicated for patients with stenosis less than 50%. For the symptomatic patients with stenosis between 50 and 69%, CEA is moderately useful and can be considered in selected patients. There is increasing evidence that specific plaque morphological features, such as “soft” noncalcific plaque with intraplaque hemorrhage and ulceration, increase the risk of stroke, and CEA may be a treatment option in symptomatic patients with only moderate degrees of ICA stenosis. NASCET showed that in symptomatic patients with stenosis of 50–69%, the 5-year rate of ipsilateral stroke in the surgical group was 15.7% compared to 22.2% among those treated medically.

For patients with asymptomatic ICA stenosis from 60 to 99%, evidence from the Asymptomatic Carotid Atherosclerosis Study (ACAS) and Asymptomatic Carotid Surgery Trial (ACST) showed a modest benefit favoring CEA, with an absolute risk reduction at 5 years of 5.9% and 5.4%, respectively. The stroke risk reduction was more prominent in men and independent of the degree of stenosis or contralateral disease. Therefore, it is reasonable to consider CEA for asymptomatic stenosis of 60–99% if the patient has a life expectancy of at least 5 years and if the rate of perioperative stroke or death for the institution or particular surgeon can be reliably kept to less than 3%.

Carotid endarterectomy is one of the more common vascular procedures, with rates of perioperative mortality or stroke below 1% now achieved in many centers or practices (Fig. 55-14). A complication rate of less than 3–5% is thought to ensure overall patient benefit and most go home 1 or 2 days following surgery. Postoperative cranial neuropathies, cardiac complications, hyperperfusion syndrome with intracranial hemorrhages and rarely seizures can also occur but are rare.

Figure 55-14 Endarterectomy for Extracranial Carotid Artery Atherosclerosis.

Rehabilitation

Advances in basic and clinical research have shown that the human brain is capable of significant recovery after stroke, provided appropriate rehabilitation treatment is applied at the right amount and time. Several new techniques have become available in the past decade, such as task-specific therapy, robotic-assisted rehabilitation, and constraint-induced movement therapy with ongoing studies about their short- and long-term efficacy.

Task-specific therapy is specifically designed to deal with loss of particular abilities and seems to be more efficacious than traditional approaches for patients with motor deficits. Robotic-assisted rehabilitation, especially for the upper extremities, has been shown to reduce even severe motor impairment in stroke patients. Constraint-induced movement therapy, where the unaffected arm is restrained while the paralyzed limb is left to perform intense exercises over 2 consecutive weeks, has shown a statistically and clinically significant improvement in motor arm function as compared with traditional therapy. Persistent benefits up to 2 years have been reported.

Future Directions

Modern technology has improved the understanding of stroke and TIA pathophysiology, which will translate into a more rational therapeutic approach.

Emerging therapies being evaluated for secondary prevention of atherothromboembolism include P2Y12 ADP receptor antagonists, thromboxane receptor antagonists, and thrombin receptor antagonists. The oral direct thrombin antagonist Dabigatran has recently emerged as an alternative to warfarin for atrial fibrillation with similar efficacy in stroke prevention and a decreased incidence of major bleeding complications in general. Unlike with warfarin, frequent dose adjustments and blood monitoring are not needed. Although Dabigatran promises to replace warfarin in the future, its current disadvantages include higher cost and slightly increased MI rates; also, it remains unclear how to best reverse its effects in cases of emergency.

Endovascular techniques, such as angioplasty and stents (Fig. 55-15), will likely change the management approach for some patients with extracranial and intracranial disease. The recent Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) shows similar outcomes with carotid artery stenting (CAS) and CEA for the treatment of symptomatic and asymptomatic carotid stenosis (vascular event or death: 7.2% vs 6.8% at 2.5 years). However, 30-day stroke rates were significantly higher for stenting (4.1% vs 2.3%), whereas MI rates were higher for CEA (2.3% vs 1.1%). The choice of procedure therefore depends on a careful consideration of co-morbidities, individual risks, institutional experience, and patient preference.