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.

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