CHAPTER 94: CEREBROVASCULAR DISEASE AND NEUROLOGIC MANIFESTATIONS OF HEART DISEASE

Many vascular diseases affect both the heart and the brain. Cardiac diseases often lead to lesions and dysfunction within the brain, and central nervous system (CNS) diseases can influence the heart and its function

Stroke is a common and devastating disease, the fifth leading cause of death and the leading cause of disability in the United States. On average, one American dies from a stroke every 4 minutes. Cardiogenic stroke can occur when (1) the heart pumps unwanted material into the circulation that reaches the brain (embolism), (2) pump function fails and the brain is hypoperfused, or (3) drugs given to treat cardiac disease have adverse neurologic effects.

Direct Cardiogenic Brain Embolism

Etiology

Cardiogenic cerebral embolism is responsible for approximately 20% of ischemic strokes.^1,2,3,4,5 Because many patients have coexisting cardiac and extracranial vascular disease,⁵ criteria for the diagnosis of cardiac embolism remain controversial even today. As more advanced diagnostic techniques have been developed, more causative cardiac abnormalities (and their association with stroke) have been recognized. Cardiac sources of brain emboli can be divided into several groups⁶:

1. Arrhythmias

2. Cardiac wall and chamber abnormalities

3. Valve disorders

4. Cardiac tumors

5. Aortic arch disease

Some cardiac sources have much higher rates of initial and recurrent embolism. The more common sources will be reviewed. The Stroke Data Bank⁷ in 1992 divided potential sources of brain embolism into strong sources (prosthetic valves, atrial fibrillation [AF], endocarditis, sick sinus syndrome, ventricular aneurysm, akinetic segments, mural thrombi, cardiomyopathy, and diffuse ventricular hypokinesia) and weak sources (myocardial infarct > 6 months old, aortic and mitral stenosis and regurgitation, congestive failure, mitral valve prolapse, mitral annulus calcification, and hypokinetic ventricular segments). Patients who have these weak sources are now often lumped within a category called cryptogenic stroke or cryptogenic embolism. The sources then deemed weak were frequent findings in patients who did not have brain embolism. Research is now directed into defining the frequency of these sources and identifying ways to determine in which patients they are the embolic source and in whom they are incidental findings. The risk of embolism varies within individual cardiac abnormalities depending on many factors. For example, in patients with AF, associated heart disease, patient age, duration, chronic versus intermittent fibrillation, and atrial size all influence embolic risk. The presence of a potential cardiac source of embolism does not mean that a stroke was caused by an embolus from the heart. Coexistent occlusive cerebrovascular disease is common. In the Lausanne Stroke Registry, among patients with potential cardiac embolic sources, 11% of patients had severe cervicocranial vascular occlusive disease (> 75% stenosis) and 40% had mild-to-moderate stenosis proximal to brain infarcts.⁵

Atrial Fibrillation

Persistent and paroxysmal AF is a potent predictor of first and recurrent stroke, affecting more than 2.7 million Americans. The principal adverse consequence of AF is ischemic stroke, with AF patients being five times more likely to have a stroke than those without AF. In patients with brain emboli caused by a cardiac source, there is a history of nonvalvular AF in roughly one-half of all cases, of left ventricular (LV) thrombus in almost one-third, and of valvular heart disease in one-fourth.^1,8 Stroke prevention in patients with AF and other heart diseases is discussed later in this chapter.

Intracavitary Thrombus

Patients with large anterior myocardial infarctions (MIs) associated with a LV ejection fraction < 40% and anteroapical wall-motion abnormalities are at increased risk for developing mural thrombus caused by stasis of blood in the ventricular cavity as well as endocardial injury with associated inflammation.^2,8 Ventricular thrombi can also occur in patients with chronic ventricular dysfunction caused by coronary disease, hypertension, and dilated cardiomyopathy. Stroke is less common among uncomplicated MI patients but can occur in up to 12% of patients with acute MI complicated by a LV thrombus. The rate of stroke is higher in patients with anterior rather than inferior infarcts, and may reach up to 20% in those with large anteroseptal MI. The incidence of embolism is highest during the period of active thrombus formation during the first 1 to 3 months, with substantial risk remaining even beyond the acute phase in patients with persistent myocardial dysfunction, congestive heart failure, or AF.^8,9

Congestive Heart Failure

Current data indicate that congestive heart failure affects an estimated 5.1 million Americans. Patients with ischemic and nonischemic dilated cardiomyopathy have a similarly increased stroke risk by a factor of 2 to 3, accounting for an estimated 10% of ischemic strokes.^3,8,10 Stroke rates may be higher in certain subgroups, including patients with prior stroke or trasient ischemic attack (TIA), lower ejection fraction, LV noncompaction, peripartum cardiomyopathy, and Chagas heart disease.⁸ The 5-year recurrent stroke rate in patients with cardiac failure has been reported to be as high as 45%.^8,11

Valvular Heart Disease

The magnitude of risk for brain embolism from a diseased heart valve depends on the nature and the severity of the disease. Atrial fibrillation often coexists with valve disease.

Mitral Stenosis/Rheumatic Mitral Valve Disease

Mitral stenosis is most commonly caused by rheumatic fever. The main proximate cause for embolic stroke in mitral stenosis of any cause is AF. Other factors associated with increased stroke risk in mitral stenosis patients include older age, left atrial enlargement, reduced cardiac output, and prior embolic event. In older studies prior to the era of chronic anticoagulation, recurrent embolism was reported in 30% to 60%.^{8,11,12,13,14} Between 60% and 65% of these recurrences developed the first year, many within the first 6 months.^8,12,13 The majority of patients in these studies did have AF. Mitral valvuloplasty does not appear to eliminate the risk of embolism.^8,15

Mitral Valve Prolapse

Mitral valve prolapse (MVP) is the most common form of valve disease in adults and is generally benign.^17,18 MVP as a source of embolic stroke continues to be controversial.^6,19 Several small clinical series have reported cerebral embolism in MVP patients who lacked other possible embolic sources.^19,20,21,22 In the absence of AF, MVP/mitral regurgitation is probably not associated with a significant increase in the risk of first or recurrent stroke.^8,21,22

Mitral Annulus Calcification

Several series suggest a relation between mitral annulus calcification (MAC) and brain emboli and stroke.^3,6,23,24,25 In the Framingham Heart Study, MAC was associated with an increased risk for all types of stroke over 8 years of observation; however, only 63% were embolic and a portion of those were also associated with AF. Other population-based studies did not reveal a significant association. The association between MAC and increased risk of stroke may be the result of shared risk factors rather than direct causation. For example, AF can occur 12 times more often in patients with MAC than in those without MAC.^18,26

Aortic Valve Disease

Neither aortic regurgitation nor aortic stenosis is associated with an increased risk of first or recurrent stroke. Additionally, studies of lesser degrees of aortic valve disease, including aortic annular calcification and aortic valve sclerosis, have also not confirmed an association with an increased risk of stroke.^27,28

Other Causes of Embolism

Stroke in many patients remains cryptogenic, and more patients may have cardiogenic embolism than are recognized. Clinical features and brain investigations such as computed tomography (CT), magnetic resonance imaging (MRI), and angiography (CT angiography [CTA], magnetic resonance [MR] angiography [MRA], and digital subtraction angiography) may suggest emboli, but often a clear source is unidentified. These cases, which are termed infarcts of unknown causes in the Stroke Data Bank,^29,30,31 include as many as 40% of all stroke patients.

Fibrous and fibrinous lesions of the heart valves and endocardium are associated with certain medical conditions, with the specific stroke risk depending on the underlying medical condition.⁶ Valve lesions occur in patients with systemic lupus erythematosus (Libman-Sacks endocarditis³²), antiphospholipid antibody syndrome,³³ cancer, and other debilitating diseases (nonbacterial thrombotic endocarditis). Mobile fibrous strands are also often found during echocardiography.^6,34,35,36 Fibrin-platelet aggregates may attach to these fibrous and fibrinous lesions.

Embolic complications are common in patients who have infective endocarditis.^6,37 Mycotic aneurysms can cause fatal subarachnoid bleeding. Bleeding can also result from vascular necrosis as a result of an infected embolus.³⁷ Embolization usually stops when infection is controlled.³⁴ Warfarin does not prevent embolization and is contraindicated in patients with endocarditis and known cerebral embolism, unless there are other important lesions such as prosthetic valves or pulmonary embolism. In children and young adults with congenital heart defects, especially those with right-to-left shunts and polycythemia, brain abscess is an important complication.

Emboli often arise from sources other than the heart, such as the aorta, proximal arteries (intra-arterial or so-called local embolism), leg veins (paradoxical emboli), fat in the liver or bones (fat embolism), and materials introduced by the patient or physician (drug particles or air).⁶ The types of embolic materials vary (Table 94–1).^6,38 Atheromatous plaques in the aortic arch and ascending aorta are an important source of embolism to the brain (Figs. 94–1 and 94–2). Ulcerated atheromatous plaques are often found at necropsy in patients with ischemic strokes, especially in those in whom the stroke etiology was not determined during life.³⁹ Transesophageal echocardiography (TEE) often shows these atheromas, but technical factors limit visualization of the entire arch.⁴⁰ Large (> 4 mm), protruding mobile aortic atheromas are especially likely to cause embolic strokes and are associated with a high rate of recurrent strokes.^41,42 Use of oral anticoagulants rather than antiplatelet agents is recommended in these patients.^18,43,44

Clinical Onset and Course

Warning signs of stroke can include sudden hemiparesis, hemisensory loss, confusion, trouble speaking or understanding, visual loss, diplopia, ataxia, vertigo, or sudden severe headache with no known cause. Most embolic events occur during activities of daily living, but some embolic strokes have their onset during rest or sleep. Sudden coughing, sneezing, or nighttime micturation can precipitate embolism.^6,45 Although the deficit is most often maximal at outset, 11% of embolic stroke patients in the Harvard Stroke Registry had a stuttering or stepwise course, whereas 10% had fluctuations or progressive deficits. Later progression, if it occurs, is usually within the first 48 hours. Progression is usually caused by distal passage of emboli. As in all large infarcts, brain edema and swelling may develop during the 24 to 72 hours after stroke with headache, decreased alertness, and worsening of neurologic signs. The edema is often cytotoxic (inside cells) and usually does not respond to corticosteroid treatment.

Diagnostic Testing

Emboli usually cause occlusion of distal branches and produce surface infarcts that are roughly triangular, with the apex of the triangle pointing inward. CT and MRI findings can suggest that an ischemic stroke was cardioembolic by the location and shape of the lesions on imaging⁴⁶; eg, finding the presence of superficial wedge-shaped infarcts in multiple different vascular territories, hemorrhagic infarction, as well as visualization of thrombi within arteries. Among 60 patients with cardiogenic sources of embolism studied by CT in whom occlusive atherosclerotic cerebrovascular disease had been excluded, 56 had superficial large or small cortical or subcortical infarcts and only 4 had deep infarcts.⁴⁶ Emboli can also block the middle cerebral artery leading to solely deep infarcts, as a result of collateral flow preservation of superficial cerebral arterial flow.^6,45,47 Tiny emboli may also cause small deep or superficial infarcts.

MRI, particularly with the use of MR diffusion-weighted and MR gradient recall echo (GRE) imaging, is much more sensitive for detection of acute brain infarcts than is CT. MR is also superior in detecting hemorrhagic infarction by imaging hemosiderin. Hemorrhagic infarction has long been considered characteristic of embolism, especially when the artery leading to the infarct is patent.⁴⁸ The mechanism of hemorrhagic infarction is reperfusion of ischemic zones after iatrogenic opening of an occluded artery (eg, endarterectomy, fibrinolytic treatment) or after restoration of the circulation after a period of systemic hypoperfusion. Hemorrhage then occurs into proximal reperfused regions of brain infarcts.^6,45,49 At times, it is also possible to image the acute embolus on CT and also via MRI.^6,50,51,52

In unselected series of stroke patients, transthoracic echocardiography (TTE) has been variably useful in detecting sources.^6,53,54,55 TTE is useful in patients with known cardiac disease to clarify potential embolic sources and heart function,⁴⁵ in young patients without stroke risk factors, and in stroke patients who do not have lacunar infarction or ultrasound or CTA evidence of intrinsic atherostenosis of a major extracranial and intracranial artery. TEE provides much better visualization of the aorta, atria, cardiac valves, and septal regions. Reports of TEE suggest that the diagnostic yield is 2 to 10 times that of TTE.^56,57,58,59 Aortic plaques, atrial septal aneurysms, and atrial septal defects are also much better seen with TEE (Fig. 94–3). The use of an echo-enhancing agent such as agitated saline or echogenic contrast helps detect intracardiac shunts.

Echocardiography has definite limitations. Particles the size of 2 mm can block major brain arteries, but are beyond the imaging resolution of current echocardiographic technology.⁶⁰ Also, thromboembolism is a dynamic process. When a clot forms in the heart and embolizes, there may be no residual evidence unless a clot reforms.^6,38 Cardiac thrombi are imaged differently on sequential echocardiograms^6,64; even large thrombi once seen on one echocardiogram can disappear later.⁶¹

Cerebral embolic signals can also be detected by monitoring with transcranial Doppler (TCD).^6,62,63 Embolic particles passing under TCD probes produce transient, short-duration, high-intensity signals referred to as HITSs (high-intensity transient signals). Examples of HITSs are shown in Figs. 94–4 and 94–5. TCD monitoring of patients with AF,⁶⁴ cardiac surgery,⁶⁵ prosthetic valves, LV assist devices,⁶⁶ carotid artery disease, during carotid endarterectomy, and in stroke patients with a patent foramen ovale have shown a relatively high frequency of embolic signals.⁶⁷ Monitoring of emboli with TCD may help guide treatment decisions.

Prevention and Treatment of Direct Cardiogenic Brain Embolism

Atrial Fibrillation: Treatment Options

Warfarin

Multiple studies have showed warfarin to be effective in preventing brain embolism in patients with both rheumatic mitral stenosis and AF. Anticoagulation reduces the risk of ischemic stroke (and other embolic events) by about two-thirds, irrespective of baseline risk. The intensity of anticoagulation was higher in early studies than that currently used, and brain hemorrhages and other bleeding complications were common. Trials have now shown that lower-dose warfarin (international normalized ratio [INR] 2.0-3.0) is effective in preventing brain emboli in patients with nonrheumatic AF.

In the Copenhagen Atrial Fibrillation, Aspirin, Anticoagulation (AFASAK) study, 1007 patients (median age, 74.2 years) with chronic, nonrheumatic AF were assigned to warfarin (INR 2.8-4.2), aspirin (75 mg/d), or placebo.⁶⁸ The study was halted prematurely when analysis of effectiveness reached a predetermined level of significance in favor of warfarin treatment. The principal outcome was the composite of ischemic or hemorrhagic stroke, TIA, and systemic embolism. The observed reduction for warfarin compared with placebo was 64%, an absolute risk reduction of 3.5% per year. An analysis by intention to treat, which excluded TIA and minor stroke, indicated a risk reduction of approximately 50% (P < .05) and an absolute reduction of approximately 1.5% per year.

The Stroke Prevention in Atrial Fibrillation (SPAF) study investigators evaluated warfarin and aspirin in patients with nonrheumatic AF.^69,70,71 The study evaluated two groups of patients based on their eligibility for warfarin. In the first group, 627 patients judged eligible for warfarin were randomized to open-label warfarin (INR 2.8-4.5; prothrombin time [PT], 1.3-1.8 times control) or, in a double-blinded fashion, to either aspirin (325 mg daily, enteric coated) or a matching placebo. In the second group, 703 patients considered ineligible for warfarin were randomized (double blind) to aspirin (325 mg daily, enteric coated) or placebo. The principal outcome, a composite of ischemic stroke and systemic embolism, was significantly decreased during a mean follow-up of 1.3 years. The outcome of disabling ischemic stroke or vascular death was reduced by warfarin by 54% (P = .11), an absolute reduction of 2.6% per year. The outcome of disabling stroke or death was reduced 22% by aspirin (P = .33), an absolute reduction of approximately 1% per year. The SPAF investigators later compared low-intensity, fixed-dose warfarin (INR 1.2-1.5) plus aspirin (325 mg/d) with adjusted-dose warfarin (INR 2.0-3.0) in elderly patients with one or more risk factors for embolism.⁷¹ Ischemic stroke and systemic embolism were present in 7.9% of patients on fixed-dose warfarin plus aspirin versus only 1.9% of patients on adjusted-dose warfarin. SPAF investigators later studied the effectiveness of aspirin 325 mg in patients with low risk and found that the rate of ischemic stroke was low (2% per year).⁷²

The SPAF study identified three risk factors for thromboembolism: (1) recent congestive heart failure, (2) history of hypertension, and (3) previous thromboembolism.^73,74 The study also suggested that anticoagulation with warfarin was not indicated in patients with none of the three risk factors who were at low risk for thromboembolism (2.5% per year). SPAF investigators concluded that in such patients, the dangers of anticoagulant therapy may outweigh its benefits. Aspirin (325 mg daily) is probably reasonable and safe therapy for patients with lone, nonrheumatic AF, who are younger than 60 years of age, and have none of the three identified risk factors.^73,74,75 In all other patients with AF, long-term oral warfarin therapy (INR 2.0-3.0) is recommended unless contraindicated.^72,75

In the Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF), 420 patients with nonrheumatic AF (mean age, 68 years) were randomized unblinded to warfarin (target PT ratio, 1.2:1.5 × control; INR 1.5-2.7) or to a control group who were allowed to take aspirin.⁷⁶ The principal outcome was ischemic stroke or systemic embolism, and the mean follow-up time was 2.2 years. The incidence of stroke was reduced by 86% in the warfarin group compared with the control group (P = .002), equivalent to an absolute risk reduction of 2.6% per year. There was no demonstrable benefit of aspirin, but the study was not designed to test aspirin.

Although many trials showed the superiority of adjusted-dose warfarin over antiplatelet therapy for stroke prevention, participants in those trials tended to be younger (typically 70 years old) than the AF patients now commonly encountered in clinical practice (typically late 70s with a substantial fraction of octogenarians). The Birmingham Atrial Fibrillation Treatment in the Aged (BAFTA) trial addressed this issue, randomizing 973 AF patients aged ≥ 75 years to adjusted-dose warfarin versus aspirin 75 mg/d. The stroke rate was 5% on aspirin and nearly halved by warfarin. Surprisingly, major hemorrhage rates were similar in both groups, but 40% of patients had received warfarin previously, potentially biasing toward lower bleeding rates. The investigators concluded that “these data lend support to the use of anticoagulation for all people aged over 75 years who have AF, unless there are contraindications or the patient decides that the size of the benefit is not worth the inconvenience of treatment.”⁷⁷

Warfarin is approximately 50% more effective than aspirin in preventing stroke in patients with AF who do not have valvular disease. Data suggest that the optimal intensity of oral anticoagulation for stroke prevention in patients with AF appears to be a target INR of 2.0 to 3.0. However, the narrow therapeutic margin of warfarin, in addition to associated food and drug interactions, requires frequent INR testing and dosage adjustments. These liabilities likely contribute to underuse of warfarin, and alternative therapies are needed.

Antiplatelet Agents

The Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE) evaluated the safety and efficacy of the combination of aspirin plus clopidogrel in AF patients who were unsuitable candidates for vitamin K antagonist therapy. In those patients, the addition of clopidogrel to aspirin did reduce the risk of major vascular events, especially stroke, but also increased the risk of major hemorrhage.⁷⁸

Novel Oral Anticoagulants (NOACs)

1. Oral direct thrombin inhibitors (DTIs): Dabigatran etexilate

2. Oral direct factor Xa inhibitors: Apixaban, rivaroxaban, otamixaban, betrixaban, and edoxaban

DTIs prevent thrombin from cleaving fibrinogen into fibrin. They bind to thrombin directly, rather than by enhancing the activity of antithrombin, as is done by heparin. The only oral DTI available for clinical use is dabigatran etexilate. Another oral agent, ximelagatran, was tested, but development was discontinued in 2006 because of hepatotoxicity and cardiovascular events.

Dabigatran has been compared with warfarin in the landmark RE-LY trial, which was an open, prospective, randomized study, with blinded adjudication of events. In this trial, 18,113 patients with AF were assigned to dabigatran 110 mg twice a day, dabigatran 150 mg twice a day, or adjusted-dose warfarin. There was a trend for less MI with warfarin. Compared to warfarin, dabigatran 110 mg twice a day had similar efficacy in terms of stroke rates, with fewer major bleeds and fewer hospitalizations. Dabigatran given at 150 mg twice a day had a lower stroke rate compared with warfarin, with less mortality but similar major bleeding rates. Of note, dyspepsia, dysmotility, and gastrointestinal reflux were twice as common in those who received dabigatran.⁷⁹

Direct factor Xa inhibitors prevent factor Xa from cleaving prothrombin to thrombin. They bind directly to factor Xa, rather than enhancing the activity of antithrombin III. Examples of oral direct factor Xa inhibitors include apixaban, rivaroxaban, otamixaban, betrixaban, and edoxaban. The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study was a prospective, randomized, double-blind, multicenter, event-driven, noninferiority study comparing the efficacy and safety of rivaroxaban, an oral, once-daily, direct factor Xa inhibitor, with adjusted-dose warfarin in patients with nonvalvular AF.⁸⁰ Additionally, a different factor Xa inhibitor, apixaban, was also compared with warfarin in the ARISTOTLE trial.⁸¹

Ruff and colleagues (2014) performed the first meta-analysis of four novel oral anticoagulants: dabigatran, rivaroxaban, apixaban, and edoxaban.⁸² Anticoagulation with each of these NOACs led to similar or lower rates both of ischemic stroke and major bleeding compared to adjusted-dose warfarin (INR 2.0-3.0) in patients with nonvalvular AF. Important additional advantages of the NOAC agents are convenience (no requirement for routine testing of the INR), a high relative but small absolute reduction in the risk of intracerebral hemorrhage (ICH), lack of susceptibility to dietary interactions, and reduced susceptibility to drug interactions. Disadvantages include lack of efficacy and safety data in patients with chronic severe kidney disease, lack of easily available monitoring of blood levels and compliance, higher cost, variable availability of agents that can reverse NOAC anticoagulation, as well as the potential for unanticipated side effects, which will subsequently become evident.^79,80,81,82

Additional meta-analyses have pooled the results from the RE-LY, ARISTOTLE, ROCKET AF, and ENGAGE AF-TIMI 48 trial and come to similar conclusions.^{79,80,81,82,83,84,85,86} More recently, a 2014 Cochrane review compared the following factor Xa inhibitors to warfarin in patients with AF: apixaban, betrixaban, darexaban, edoxaban, idraparinux, and rivaroxaban. A lower rate of stroke and systemic embolic events was found with the NOACs, as well a lower rate of death and ICH.⁸⁷ A second 2014 Cochrane review evaluated studies that compared direct thrombin inhibitors to warfarin and found no significant difference in the odds of vascular death and ischemic events.⁸⁸ Fatal and nonfatal major bleeding events, including hemorrhagic strokes, were less frequent with these agents.

These meta-analyses support the broad concept that NOAC agents (direct thrombin and factor Xa inhibitors) are preferable to warfarin use in patients with AF. However, they cannot directly compare the relative advantages and disadvantages of the individual agents nor can they demonstrate whether the agents are equal in safety and efficacy. Also, the NOACs were studied in nonvalvular AF, and as a result, they are only approved for use in nonvalvular AF.

Summary

There is no single perfect medication choice for patients with AF. The authors assert that a variety of factors should influence a physician’s selection of therapy for their patient. Assessing a particular patient’s risk of ischemic stroke with CHA2DS-VASc scoring can assist in making a treatment decision between antiplatelet, warfarin, and a NOAC.⁸⁹ For example, current 2014 American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Rhythm Society (HRS) guidelines note that for patients with a CHA2DS2-VASc score of 0, antithrombotic therapy may be omitted (class IIa, level of evidence B).⁹⁰ Additionally, assessing the patient’s risk of significant bleeding with HAS-BLED scoring can also influence medication choice.⁹¹ We recommend that therapy should be tailored to the individual patient and their specific needs, including making an assessment of other comorbid medical issues, cost of the particular agent selected, history of patient compliance with medications, as well as patient preference.

Other Cardiac Causes

The effectiveness of anticoagulation on embolic stroke prevention from other cardiac conditions has not been well studied. Current AHA/American Stroke Association (ASA) guidelines recommend the following in patients with ischemic stroke or TIA in the setting of MI with LV thrombus or apical wall-motion abnormality⁸:

1. Treatment with warfarin (target INR, 2.5; range, 2.0-3.0) for 3 months is recommended in most patients with ischemic stroke or TIA in the setting of acute MI complicated by LV mural thrombus formation identified by echocardiography or another imaging modality (class I; level of evidence C). Additional antiplatelet therapy for cardiac protection may be guided by recommendations such as those from the American College of Chest Physicians (ACCP).

2. Treatment with warfarin (target INR, 2.5; range, 2.0-3.0) for 3 months may be considered in patients with ischemic stroke or TIA in the setting of acute anterior ST-segment elevation MI (STEMI) without demonstrable LV mural thrombus formation but with anterior apical akinesis or dyskinesis identified by echocardiography or other imaging modality (class IIb; level of evidence C).

3. In patients with ischemic stroke or TIA in the setting of acute MI complicated by LV mural thrombus formation or anterior or apical wall-motion abnormalities with an LV ejection fraction < 40% who are intolerant to vitamin K antagonist (VKA) therapy because of nonhemorrhagic adverse events, treatment witha low molecular weight heparin (LMWH), dabigatran, rivaroxaban, or apixaban for 3 months may be considered as an alternative to VKA therapy for prevention of recurrent stroke or TIA (class IIb; level of evidence C).

Warfarin may not be effective in preventing calcific, myxomatous, bacterial, and fibrin-platelet emboli, and warfarin has been posited to worsen cholesterol crystal embolization.⁹²

Timing of Warfarin Initiation After Embolic Stroke

Additionally the timing of the initiation of warfarin anticoagulation after embolic stroke remains controversial. Embolic brain infarcts often become hemorrhagic, and serious brain hemorrhage has occurred after anticoagulation.^93,94,95 Large infarcts, hypertension, large bolus doses of heparin, and excessive anticoagulation have been associated with hemorrhage. Because most hemorrhagic transformations occur within 48 hours, the recommendations of the Cerebral Embolism Task Force were to avoid early anticoagulation in patients with large infarcts or hemorrhagic transformation on repeat CT.^96,97 Studies of patients with cerebral and cerebellar hemorrhagic infarction show that, in the vast majority, the cause is embolic, with hemorrhagic infarction occuring equally with and without anticoagulation. The development of hemorrhagic infarction is rarely accompanied by clinical worsening.^98,99 Patients with hemorrhagic transformation who were continued on anticoagulants in general did not worsen. The risk of re-embolism must be balanced against the small, but definite, risk of important bleeding. However, if the patient has a large brain infarct, heparin should be delayed, and bolus heparin infusions should be avoided. If the risk for re-embolism is high, immediate heparinization is advisable; whereas if the risk seems low, it is prudent to delay anticoagulants for at least 48 hours. One study showed that patients with AF with embolic strokes who were treated with well-controlled heparin anticoagulation soon after stroke onset fared better than patients treated later.^100,101

Paradoxical Embolism

Cryptogenic strokes, or strokes without a clear determined cause, remain a major challenge. Paradoxical embolism has been strongly implicated as one potential cause of cryptogenic stroke. Although once considered rare, emboli entering the systemic circulation through right-to-left shunting of blood are now often recognized with the advent of newer diagnostic technologies. By far the most common potential intracardiac shunt is a residual patent foramen ovale (PFO). The high frequency of PFOs in the normal adult population has made it difficult to be certain in an individual stroke patient with a PFO whether paradoxical embolism through the PFO was the cause of the stroke or whether the PFO was merely an incidental finding. Autopsy series have shown that approximately 30% of adults have a probe PFO at necropsy.¹⁰² Echocardiographic studies have shown that PFOs are more common in patients with an undetermined cause of stroke than in those in whom another etiology has been defined.^103,104 Lechat and coworkers,¹⁰³ using TTE with contrast injection during Valsalva maneuver, demonstrated right-to-left shunting through a PFO in 56% of patients with cryptogenic stroke, in comparison to 10% of the patients in the control group. Webster and colleagues,¹⁰⁵ in a study of stroke patients younger than 40 years of age, found a PFO in 50% of patients with stroke using contrast echocardiography.

Neuroimaging studies are not conclusive with regard to the link between PFO and embolic stroke. However, in 1998, Steiner and colleagues¹⁰⁶ reported on a series of 95 patients with first stroke and who had PFOs. Those with large PFOs had more features of embolic strokes with brain imaging than did patients with small PFOs.

Review of series of patients with paradoxical embolism^107,108,109 through a PFO and the authors’ experience allow the derivation of five criteria that, when four or more are met, establish the presence of paradoxical embolism with a high degree of certainty⁶:

1. Situations that promote thrombosis of the deep veins of the leg or pelvis (eg, long sitting in one position, such as prolonged airplane flight, or recent surgery).

2. Increased coagulability (eg, the use of oral contraceptives, presence of factor V Leiden, dehydration, and other inherited or acquired thrombophilia).

3. The sudden onset of stroke during Valsalva or other maneuvers that promote right-to-left shunting of blood (eg, sexual intercourse, straining at stool).

4. Pulmonary embolism within a short time before or after the neurologic ischemic event.

5. The absence of other putative causes of stroke after thorough evaluation.

But the question remains: While a PFO may have contributed to the development of an ischemic stroke, is an isolated PFO capable of causing the stroke alone? The presence of an atrial septal aneurysm along with a PFO increases the risk of stroke. Among 581 patients the stroke risk was 2.3% in patients with PFO and 15.2 % in those with both PFO and atrial septal aneyrysm.^109a The Risk of Paradoxical Embolism (RoPE) study performed a patient-level meta-analysis of 12 cryptogenic stroke cohorts.^110,111 Among 3023 patients with cryptogenic stroke, the prevalence of PFO, and the likelihood that PFO was the cause of the stroke (the PFO-attributable fraction), correlated with the absence of vascular risk factors (ie, hypertension, diabetes, smoking, prior stroke or TIA, older age) and the presence of a cortical (as opposed to subcortical) cryptogenic infarct on imaging.¹¹⁰ Using multivariate modeling, the investigators devised the RoPE score, which estimates the probability that a PFO is either incidental or pathogenic in a patient with cryptogenic stroke.¹¹⁰ High RoPE scores, as found in younger patients who lack vascular risk factors and have a cortical infarct on neuroimaging, suggest pathogenic PFOs, while low RoPE scores, as found in older patients with vascular risk factors, suggest incidental PFOs. For each RoPE score stratum, the corresponding PFO prevalence was used to estimate the PFO-attributable fraction: the probability that the index event was related to the PFO. In a subsequent analysis, stroke recurrence was associated with the following three variables only in the high RoPE score group: a history of prior stroke or TIA, a hypermobile interatrial septum (atrial septal aneurysm), and a small shunt.¹¹¹ The RoPE data did not include activity at onset; strokes that develop suddenly during sex, straining at stool, and Valsalva maneuvers and sudden exertion are often embolic.

In the author’s opinion, the following evaluation should be done in patients with acute stroke who are also found to have PFO to attempt to ensure there are no other causes for the stroke:

1. Brain imaging: MRI of brain without contrast if possible, CT of head without contrast if obtaining an MRI is prohibitory.

2. Vascular imaging: CTA of head and neck or MRA of head and neck or Duplex of the carotid arteries and TCD of head.

3. TEE with bubble study.

4. Hypercoagulable work-up: protein C, protein S, activated protein C resistance (if positive, test for factor V Leiden), dilute Russell viper venom time, cardiolipin antibody (if positive, test beta-2 glycoprotein 1 antibody), prothrombin gene mutation, antithrombin III, homocysteine

5. Other laboratory work-up: cholesterol panel, HBA1C, PT, INR, partial thromboplastin time, complete blood count, Chem7, troponin × 3, erythrocyte sedimentation rate. If patient is febrile or there is risk for endocarditis: blood cultures × 3.

6. Electrocardiogram (ECG).

7. Holter monitor, and if negative, longer monitoring as an outpatient for occult arrhythmia.

Current treatment options for future stroke prevention in patients with PFO and cryptogenic ischemic stroke include medical therapy, open or minimally invasive cardiac surgical closure, and transcatheter closure. Before any treatment option is selected, it is again important to confirm that the stroke is indeed cryptogenic. The treating physician should exclude all other possible contributing causes to the stroke, including a coexisting hypercoagulable state and deep venous thrombosis (with or without May-Thurner syndrome).^113,114 If there is concomitant hypercoagulability or deep venous thrombosis, anticoagulation is the treatment of choice for these conditions as well as to prevent further ischemic stroke.

Once this has been done, with regard to medical therapies, antiplatelet therapy has always been considered reasonable for future stroke prevention in cryptogenic stroke patients with a first ischemic stroke/TIA plus an isolated PFO. In patients with a cryptogenic stroke and an atrial septal aneurysm, evidence had been insufficient to determine whether warfarin or aspirin is superior in preventing recurrent stroke or death. Warfarin is considered to be an appropriate treatment option in the subgroup of PFO/ischemic stroke patients with concomitant hypercoagulable state or venous thrombosis.

An alternative option is transcatheter PFO closure, a minimally invasive endovascular procedure during which a closure device is guided utilizing catheters to seal the PFO. Recently, transcatheter closure demonstrated a benefit compared to medical therapy for future stroke prevention. The RESPECT trial was a multicenter, prospective, randomized clinical trial designed to investigate whether percutaneous PFO closure, using the AMPLATZER PFO Occluder, is superior to current standard of care medical treatment in the prevention of recurrent embolic stroke. Investigators enrolled 980 patients (aged 18 to 60 years) with a PFO who experienced a cryptogenic stroke in the preceding 270 days. Patients were randomly assigned to receive either a PFO occluder (Amplatzer, AGA Medical, Golden Valley, MN; n = 499) or guideline-directed medication (n = 481). RESPECT represents the largest randomized trial on PFO closure ever conducted, with the longest-term follow-up, with a mean of 5 years and a duration of more than 10 years.¹¹⁵

Initial intent-to-treat analysis results revealed no significant difference in all-cause stroke between groups (P = .16), similar to prior PFO closure device studies. However, when strokes were restricted to cryptogenic strokes alone, Carroll and colleagues reported a 54% relative risk reduction in the PFO occlusion arm (P = .042), although the number of these strokes remained small (10 vs 19). Among patients under the age of 60 years, researchers found a 52% relative risk reduction in the PFO closure arm (P = .035). Furthermore, a 75% relative risk reduction in cryptogenic stroke was observed among PFO closure patients who had PFO characteristics of substantial shunt or atrial septal aneurysm (P = .007). In safety analysis, there were no cases of device erosion, embolization, or thrombosis, and no intra-procedure strokes. Additionally, the rate of AF was not significantly different between groups. Extended follow-up data from the RESPECT trial suggests that compared with medical management, a PFO closure device significantly decreases recurrent cryptogenic ischemic stroke in patients with PFO who had a cryptogenic stroke in the last 270 days.¹¹⁵

With regard to surgical closure of symptomatic PFO, there is no clear evidence at present that it is superior to medical or endovascular therapy for secondary stroke prevention. More recently, widespread use of intraoperative TEE during cardiac surgery has resulted in frequent discoveries of incidental asymptomatic PFOs. A recent survey by Sukernik and associates¹¹⁶ suggests that a number of cardiac surgeons in the United States alter their planned procedure to include closure of the PFO. This is concerning in light of recent data published by Krasuski and coworkers,¹¹⁷ who investigated the prevalence of intraoperative PFO diagnosis and the relationship that the incidental repair had on perioperative outcome and long-term survival. Surgeons were more likely to repair PFOs in patients who were younger, female, undergoing tricuspid or mitral surgery, had left atrial dilation, or with prior stroke and TIAs. Repair also tended to occur in patients with fewer comorbidities. Patients with incidental PFO were no more likely to have had a preprocedural stroke than patients without PFO. Postoperatively, the patients with an incidentally repaired PFO had 2.47 times greater odds of having an in-hospital, symptomatic postoperative stroke compared with those with unrepaired PFO (there was no difference in long-term survival).¹¹⁷ These findings of increased short-term postoperative stroke risk should discourage the routine closure of incidentally detected PFO for now. Further studies to assess whether any subgroup of PFO patients may benefit from closure will be important in the future.

Brain Hypoperfusion (Cardiac Pump Failure)

After cardiopulmonary resuscitation (CPR), the heart often recovers in individuals whose brain has been irreversibly damaged by ischemic-anoxic damage.¹¹⁸ Cardiologists must become very familiar with the pathology, signs, and prognosis of brain dysfunction after periods of circulatory failure.

Different brain regions have selective vulnerability to hypoxic-ischemic damage. Regions that are most remote and at the edges of major vascular supply are more liable to sustain hypoperfusion injury. These zones are usually referred to as border zones or watersheds. The cerebral cortex and hippocampus are particularly vulnerable to injury.^{119,120,121,122} In the cerebral cortex, the border zone regions are between the anterior cerebral artery (ACA) and middle cerebral artery (MCA), and between the MCA and posterior cerebral artery (PCA). The basal ganglia and thalamus are most involved if hypoxia is severe, but some circulation is preserved. This situation applies most to hanging, strangulation, drowning, and carbon monoxide exposure.¹²³ Cerebellar neurons may also be selectively injured.¹²⁴

When circulatory arrest is complete and abrupt, brainstem nuclei are especially vulnerable to necrosis in young humans and experimental animals.¹²⁵ When hypoxia and ischemia are especially severe, the spinal cord may also be damaged.^126,127 When cortical damage is severe and protracted, cytotoxic edema causes massive brain swelling, with cessation of blood flow and brain death.

Clinical Findings

Very severe hypoxic-ischemic damage can lead to mortal injury to the cortex and brainstem, irreversible coma, and brain death. When initially examined, such patients have no brainstem reflexes and no response to stimuli, except perhaps a decerebration response. These findings do not improve, and respiratory control is absent or lost.

When cerebral cortical damage is very severe, but brainstem reflexes are preserved, there is no meaningful response to the environment. Automatic facial movements such as blinking, tongue protrusion, and yawning usually persist. The eyes may rest slightly up and move from side to side. When this state does not improve, it is referred to as the persistent vegetative state^{118,121,128,129} or wakefulness without awareness. Laminar cortical necrosis can cause seizures (multifocal myoclonic twitches or jerks of the facial and limb muscles), which are difficult to control with anticonvulsants.

With severe hypoperfusion ACA-MCA border zone injury, there is weakness of the arms and proximal lower extremities with preservation of face, leg, and foot movement (the “man in a barrel” syndrome). With MCA-PCA ischemia, the symptoms and signs are predominantly visual. Patients describe difficulty seeing and inability to integrate the features of large objects or scenes despite retained capacity to see small objects in some parts of their visual fields. Reading is impossible. There are features of Balint syndrome.^118,130 Apathy, inertia, and amnesia are also common. Patients cannot make new memories and have patchy, retrograde amnesia for events during and before hospitalization. This Korsakoff-type syndrome is caused by hippocampal damage and may not be fully reversible. Amnesia may be accompanied by visual abnormalities, apathy, and confusion, or may be isolated.

Prognosis

Shortly after resuscitation or arrest, patients with less severe cerebral injuries show some reactivity to the environment. Eye opening and restless limb movements develop. The eyes may fixate on objects. Noise, a flashlight, or a gentle pinch may arouse patients to react to stimuli. Soon patients awaken fully and may begin to speak. Cognitive and behavioral abnormalities may be detected after the patient awakens, depending on the degree of injury.

Prognostic signs and variables have been extensively studied.^{118,131,132,133,134} The initial neurologic findings and their course are helpful in predicting outcome. Among patients who have meaningful responses to pain at 1 hour, almost all survivors have preserved intellectual function. Patients who do not respond to pain by 24 hours typically either die or remain in a vegetative state. Being comatose predicts a poor prognosis.^133,134 Two simple observations—the presence or absence of coma and the response to pain—predict neurologic outcome very early.¹³⁴ Recurrent myoclonus is also a poor prognostic sign.¹³⁵

In a study in Seattle of out-of-hospital cardiac arrests, patients who did not awaken died on average 3.5 days after arrest.^136,137 Of 459 patients, 183 never awakened (40%). Among those who did awaken, 91 (33%) had persistent neurologic deficits.¹³⁶ Prognosis could be made by analysis of pupillary light reflexes, eye movements, and motor responses.¹³⁷ It is unclear whether bystander initiation of CPR is significantly related to awakening.^137,138 After in-hospital CPR, pneumonia, hypotension, renal failure, cancer, and a housebound state before hospitalization were significantly related to death in the hospital.¹³⁹

Diagnostic Testing

Neuroimaging and other tests have proved to be relatively unhelpful in contrast to the neurologic examination.¹¹⁸ CT is used to exclude other causes of coma, such as brain hemorrhage. Electroencephalography is helpful in studying cortical activity in unresponsive patients. TCD may be helpful in the evaluation of brain death, but is not a requirement to determine brain death.^140,141,142

Treatment

Other than maintaining adequate circulation and oxygenation, treatment has not helped improve outcome. Increased blood sugar correlates with poor outcome.¹⁴³ A multifaceted approach to therapy has been most successful.¹⁴⁴

Neurologic Effects of Cardiac Drugs and Cardiac Encephalopathy

Drugs given to patients with cardiac disease often have neurologic adverse effects.¹⁴⁵ Digoxin can cause visual hallucinations, yellow vision, and general confusion.^146,147 Digoxin levels need not be excessively elevated; the symptoms disappear with drug cessation. Quinidine can cause delirium, seizures, coma, vertigo, tinnitus, and visual blurring.¹⁴⁸ Similar toxicity has been seen with lithium. Patients may become acutely comatose while being treated with intravenous lidocaine. This effect has been associated with the accidental administration of very large doses; more common CNS effects of less extreme toxicity include sedation, irritability, and twitching. The latter may progress to seizures accompanied by respiratory depression. Amiodarone can cause ataxia, weakness, tremors, paresthesias, visual symptoms, a Parkinsonian-like syndrome, and occasionally delirium.¹⁴⁵ The neurological side effects with amiodarone can occur even at normal doses.

Patients with congestive heart failure often develop an encephalopathy characterized by decreased alertness, sleepiness, decrease in all intellectual functions, asterixis, and variability of alertness and cognitive functions from hour to hour.¹⁴⁵ These patients may not have pulmonary, liver, or renal failure or electrolyte abnormalities. This cardiac encephalopathy is probably multifactoral.¹⁴⁵

Patients with heart disease are diagnosed, treated, and at times even cured with a variety of cardiac procedures. Although the implicit goal with any cardiac intervention (diagnostic or therapeutic) is to improve a patient’s quality of life, these procedures often carry risk as well as the possibility of benefit.

Endovascular Cardiac Diagnostic and Therapeutic Procedures

Cardiac Catheterization

Stroke and TIA are known complications of heart catheterization. In 1977, Dawson and Fischer¹⁴⁹ reported cerebrovascular complications in 10 of 1000 consecutive cardiac catheterizations. Nine out of 10 of these events were determined to be embolic.^149,150 Similarly, Mendez Dominguez and colleagues¹⁵¹ reported thromboembolic neurologic complications in seven patients in a series of 2178 consecutive cardiac catheterizations. In all cases, the cerebrovascular impairment occurred either during or within several minutes following the cardiac catheterization. All strokes were confirmed with CT or MRI, and the clinical profile in most cases supported an embolic mechanism.¹⁵¹ Central retinal artery occlusion has been reported in association with cardiac catheterization.¹⁵² More recently, Liu and coworkers¹⁵³ reported six ischemic strokes and one ICH in a series of 3648 cardiac catheterizations in children. In this study, the suspected catheterization-related stroke mechanisms included intracranial hemorrhage caused by intraprocedure anticoagulation as well as cerebral embolism from local clot.¹⁵³ Other potential mechanisms for cerebrovascular events during cardiac angiography may include catheter tip thromboembolism, atherosclerotic plaque or cholesterol embolism, air emboli, arterial vasospasm, and/or hypotension.^{150,154,155,156,157}

Coronary Artery Angioplasty and Stenting

The stroke rate in patients undergoing percutaneous coronary interventions for both stable and unstable coronary artery disease (including angioplasty for acute MI) has been reported to be between 0% and 4%.^{158,159,160,161,162,163,164,165} A combined analysis of data from four double-blind, placebo-controlled, randomized trials (EPIC, CAPTURE, EPILOG, and EPISTENT) conducted between 1991 and 1997 assessed 8555 patients undergoing various percutaneous coronary interventions. Among the 8555 patients, there were 33 strokes in 31 patients (0.36%) within 30 days. Stroke occurred in 9 (0.29%) of 3079 patients receiving percutaneous coronary interventions alone; six strokes were ischemic, and three were hemorrhagic. Stroke was diagnosed in 22 (0.41%) of 5476 patients who underwent percutaneous treatment in conjunction with abciximab treatment, of which there were 13 ischemic strokes and 9 hemorrhages.^{158,159,160,161,162,163}

Galbreath and colleagues¹⁶⁴ reported a 0.2% rate of focal central neurologic complication in their series of 1968 percutaneous transluminal coronary angioplasties; three were ischemic strokes, and one was a TIA. The mechanism in these cases was considered embolic in three patients; one patient had air inadvertently injected through the guide catheter, and two had events after the ascending aorta was scraped with the guide catheter in search of a graft ostium. The remaining patient had an event during a period of hypotension.¹⁶⁴

Electrophysiologic Procedures and Electrical Cardioversion

Thromboembolic stroke can be a complication of cardiac electrophysiologic procedures, including radiofrequency catheter ablation of arrhythmia. Multicenter data are limited; however, the stroke risk appears to be < 2%.^{150,166,167,168,169} Additionally, electrical cardioversion may be used in the treatment of AF and atrial flutter. Stroke caused by direct current cardioversion has been estimated to occur in 1.3% of cardioverted patients.¹⁷⁰ Anticoagulation before and after cardioversion lowers the risk of embolism.^150,170

Percutaneous Closure of the Left Atrial Appendage

In patients with nonvalvular AF, embolic stroke is thought to be associated with left atrial appendage (LAA) thrombi. One multicenter, randomized, noninferiority trial found that percutaneous closure of the LAA was noninferior to warfarin treatment. In the future, closure of the LAA might provide an alternative to chronic warfarin for stroke prevention in patients with nonvalvular AF.¹⁷¹ The Percutaneous Left Atrial Appendage Transcatheter Occlusion (PLAATO) study investigated percutaneous closure of the LAA in patients who were not warfarin candidates. At the 5-year follow-up, the annualized stroke/TIA rate was 3.8% per year, which was lower than predicted.¹⁷² More recent trials, such as PROTECT AF, found that after 3.8 years of follow-up among patients with nonvalvular AF at elevated risk for stroke, percutaneous LAA closure met criteria for both noninferiority and superiority, compared with warfarin, for preventing the combined outcome of stroke, systemic embolism, and cardiovascular death, as well as superiority for cardiovascular and all-cause mortality.¹⁷³

Intra-aortic Balloon Pump

Intra-aortic balloon pumps (IABPs) are used in patients with severe LV failure or cardiogenic shock. The IABP is inserted into the patient’s midthoracic aorta to maintain adequate perfusion. Spinal cord infarcts can occur in patients with IABPs caused by local thromboembolism, aortic dissection, aortic atherosclerotic plaque rupture, or local hypoperfusion.^150,174

Percutaneous Valvuloplasty

Surgical treatment, specifically valve replacement, are generally the treatment of choice for both aortic and mitral valve diseases in patients who are at acceptable risk for surgery. Aortic valvuloplasty, at present, provides only transient and modest benefit for aortic stenosis, with a significant risk of stroke and vascular injury. However, it can stabilize patients who require additional attention prior to undergoing surgery.¹⁷⁵ Additionally, over the past 5 years, percutaneous approaches to valve implantation have improved. Technical and device issues are being refined, and some percutaneous treatments are showing promise in ongoing clinical trials.¹⁷⁶ Percutaneous balloon aortic and mitral valvuloplasties have been complicated by stroke.^{150,177,178,179,180} Sudden coma has also been reported after percutaneous balloon mitral valvuloplasty.¹⁸¹ With regard to when the neurologic events occur, the 1988 series of Letac and coworkers¹⁷⁷ of 218 patients undergoing transcutaneous balloon aortic valvuloplasty indicates that one stroke occurred during the intraprocedure period, whereas three additional strokes occurred during the postprocedure period.^{150,177,178,179,180}

Transcatheter Aortic Valve Replacement

Transcatheter aortic valve replacement (TAVR) is a minimally invasive catheter-based surgical procedure for patients with severe symptomatic aortic stenosis, who are either high-risk or inoperable candidates for traditional cardiac surgery. Samim and colleagues (2015) investigated the occurrence and distribution of TAVR-related silent acute ischemic brain lesions using diffusion-weighted magnetic resonance imaging (DWI). Clinically silent cerebral infarcts occurred in 90% of patients following TAVR, most of which were small (< 20 μL) and located in the cortical regions of the cerebral hemispheres: 47% of lesions were detected in the cortical regions, 35% in the subcortical regions, and 18% in the cerebellum or brainstem. An independent association was also found between age, hyperlipidaemia, and balloon postdilatation and the number of post-TAVR ischemic brain lesions. Only peak transaortic gradient was independently associated with postprocedural total infarct volume.¹⁸²

The Placement of Aortic Transcatheter Valves (PARTNER) B trial found the rate of symptomatic stroke at 1 year among TAVR patients to be double that of patients assigned to medical therapy alone.¹⁸³ Initial presentation of the data caused concern; however, follow-up data from the same trial have demonstrated that the risk of stroke or TIA was similar between those randomized to TAVR versus surgical aotic valve replacement (AVR): 15.9% in the TAVR group compared to 14% in the surgical AVR group.¹⁸⁴ It is important to note that the incidence of symptomatic stroke post-TAVR is improving over time. A more recently published registry with 12,182 patients noted the stroke rate at 1 year to currently be 4.1%.¹⁸⁵ The mechanism for stroke in TAVR is thought to be showering of atheroemboli or calcific material during balloon predilation, valve positioning, or valve implantation.¹⁸⁶

Decreasing the TAVR risk of stroke in the future may include improving risk prediction, valve system technology, periprocedural medical therapy, and potentially through embolic protection devices.¹⁸⁶ The Embrella embolic deflection device for cerebral protection during TAVR was assessed in one small series of 15 patients (and compared to 37 patients who had previously undergone TAVR without a protection device). Use of this device actually was noted to increase the number of cerebral ischemic lesions on MRI, but there was a significant reduction in single lesion volume as well as an absense of large total infarct volumes.¹⁸⁷ Whether this reduction in lesion size correlates to improved neurological outcomes is as yet uncertain. Additional embolic protection devices have been developed, with clinical trials currently under way.¹⁸⁶

Cardiovascular Surgery

Every year, an estimated 1 million patients undergo cardiac surgery throughout the world. Coronary artery bypass graft (CABG) surgery is the most common major cardiovascular operation performed.

The frequency of abnormalities of intellectual function and behavior after cardiac surgery is high.¹⁸⁸ Preoperative diagnoses of diabetes, history of prior stroke, older age, female sex, smoking, hypertension, left main coronary disease, mild renal impairment (defined as serum creatinine 1.47-2.25 mg/dL), and high-sensitivity preoperative C-reactive protein (defined as high-sensitivity C-reactive protein concentration ≥ 3.3 mg/L) have all been identified to increase perioperative stroke risk.^{189,190,191,192} Additionally, preoperative stroke and TIA are also risk factors for in-hospital mortality.¹⁹¹

Bucerius et al’s prospective data on 16,184 consecutive patients indicate that the cerebrovascular risk depends on the procedure performed.¹⁹³ In that study, the overall incidence of stroke was 4.6% and varied between surgical procedures (CABG 3.8%; beating-heart CABG 1.9%; aortic valve surgery 4.8%; mitral valve surgery 8.8%; double or triple valve surgery 9.7%; CABG and valve surgery 7.4%). Additional studies have also estimated stroke risk for isolated CABG range as less than 3.8%.^193,194,195 A particular patient’s risk of perioperative stroke can be estimated using the Society of Thoracic Surgeons 2008 cardiac surgery risk models, which include outcomes for stroke, as well as deep sternal wound infection, reoperation, prolonged ventilation, and renal failure, among other morbidities. Several variables were forced into each model to ensure face validity (eg, the permanent stroke model includes AF as a variable).^196,197,198

Early reported studies suggested a decrease in postoperative stroke rates in patients undergoing off-pump CABG compared with patients undergoing the traditional on-pump operation, but conflicts in the literature do exist.^{199,200,201,202,203} One potential explanation for the discrepancy is that the temporal pattern of stroke after CABG was not distinguished in all studies. One single-center study of 2516 consecutive patients has noted that off-pump CABG reduced the incidence of early postoperative stroke (symptoms noted just after emergence of anesthesia). However, the risk of delayed stroke (normal neurologically emerging from anesthesia, but symptoms presenting within 30 days after surgery) was no different between the on- and off-pump CABG patients.²⁰³ Perhaps the difference in the early stroke etiology between off- and on-pump CABG could be explained by the difference in aortic clamp use between these CABG procedures.

Another reason for the discrepancies in data may be that many of the above studies also did not differentiate between clampless and partial clamp off-pump techniques. One study of 700 consecutive patients undergoing multiple-vessel off-pump CABG demonstrated a decreased incidence of stroke (0.2% vs 2.2%) in the aortic no-touch group. Additionally, logistic regression identified partial aortic clamping as the only independent predictor of stroke, increasing this risk 28-fold.²⁰⁴ Interestingly (and perhaps also a result of the difference in clamp use between on- and off-pump CABG procedures), one study also found that off-pump CABG provided a decreased risk of stroke and mortality advantages, especially for women.²⁰²

More recently in 2013, a larger trial by Lamy and colleagues reported effects of off-pump versus on-pump CABG at 1 year. The CORONARY (CABG Off or On Pump Revascularization Study) trial enrolled 4752 patients, randomly assigning them to on-pump versus off-pump CABG. Stroke rates did not differ significantly between the two groups. Quality of life and cognitive function were assessed at 30 days and 1 year. There was no significant difference in either of these two measures at 1 year.²⁰⁵

In one multicenter study, the incidence of stroke plus severe intellectual dysfunction from CABG has been reported to be 6%.²⁰⁶ With regard to combined procedures, one multicenter investigation assessing 273 patients undergoing combined CABG and left-sided cardiac procedure (such as aortic or mitral valve replacement) estimated that 15.8% of patients had neurologic complications (8.5% with stroke or TIA and 7.3% with new intellectual deterioration).²⁰⁷ This combined procedure appears to carry a higher stroke risk than CABG performed in isolation.

It is unclear whether minimally invasive cardiac surgical procedures may potentially have a lessened stroke risk because further data are needed. One study suggests that minimally invasive CABG may lessen the risk of major adverse cerebrovascular and cardiac events compared with traditional off-pump CABG.²⁰⁸ Another center’s result with direct-access, minimally invasive mitral valve surgery in 106 patients demonstrated a low rate of stroke and TIA, with a total of 0.28% of patients having either stroke or TIA. However, a second center’s results with minimally invasive, reoperative, isolated valve surgery did not show a lower stroke rate compared with patients undergoing sternotomy.^209,210

Overall, in prospective studies, transient complications have been noted in 61% of cardiac surgery patients.²¹¹ In one series in CABG patients, 16.8% had stroke or encephalopathy postoperatively; the encephalopathies usually cleared, and only 2% of patients had severe strokes.²¹² The potential mechanisms of cerebral impairment in the cardiac surgery population will be explored in the following sections.

Atherothrombotic, Hemodynamically Mediated Brain Infarcts

An estimated 12% of patients requiring CABG also have significant carotid artery disease.²⁰⁹ Whether or not symptomatic of carotid atherosclerosis, patients with high-grade carotid artery stenosis undergoing CABG surgery face a higher risk of stroke than patients without carotid disease, but most strokes are mechanistically unrelated to carotid disease.²¹³ One major concern regarding cardiac surgery patients has been whether the hemodynamic stress of heart surgery leads to underperfusion of areas supplied by already stenotic or occluded arteries, resulting in brain infarcts. This concern underlies neck auscultation for bruits, ultrasound carotid artery testing, and cerebral angiography prior to CABG. However, hemodynamically induced infarction related to preexisting atherosclerotic occlusive cervicocranial arterial disease is a rare complication of heart surgery. Asymptomatic patients with carotid bruits have a very low rate of stroke after elective surgery.^214,215 However, the risk of perioperative stroke does increase with increasing severity of carotid stenosis.^190,216,217 In a retrospective study of CABG patients with known carotid disease, ipsilateral strokes occurred in 1.1% of arteries with 50% to 90% stenosis, in 6.2% of arteries with > 90% stenosis, and in only 2% of vessels with carotid occlusion.^216,217

Uncertainty exists about whether carotid endarterectomy (CEA) performed simultaneous or prior to CABG improves perioperative stroke risk.²¹³ Stroke rates vary greatly in those undergoing combined CEA-CABG as opposed to staged procedures.^213,218 Limited published data of 324 patients suggested that early outcomes after synchronous CEA plus off-pump CABG were better than those following staged or synchronous CEA plus on-pump CABG. It is unclear whether these findings were caused by publication bias, case selection, or, as we discussed earlier in the chapter, the fact that the aorta was not manipulated or cannulated.²¹⁹

Definitive management of combined cervicocerebral and coronary artery disease awaits the outcome of clinical trials. One systematic review of 97 published studies of staged versus synchronous operations found no significant difference in outcomes between these two surgical groups. Unfortunately in this study, there were no comparable data for patients with combined carotid stenosis and cardiac disease not undergoing either staged or synchronous surgery.²²⁰ A different retrospective study of 4335 patients undergoing cardiac surgery found that undergoing a combined CEA-CABG increased the risk of postoperative stroke compared with patients with similar degrees of carotid stenosis who underwent CABG without a carotid revascularization.²²¹

Carotid artery stenting (CAS) has been recently introduced as an alternative revascularization modality in high-risk patients. Although some studies suggest that endovascular CAS for both symptomatic and asymptomatic carotid artery disease prior to CABG is safe and without an increased risk of stroke, conflicts again arise in the literature.^{222,223,224,225,226} Whether CAS should be performed prior to CABG is still a point of debate at this time.

Most studies have relied on clinical localization of focal deficits and inference about their mechanisms. A neuroradiology study reviewed neuroimaging results from 30 patients with acute strokes in relation to CABG.²²⁷ Only one had evidence of a hemodynamic atherostenotic mechanism, which supports the data suggesting that hemodynamically induced infarction during cardiac surgery is rare. Embolism arising from cardiac and aortic sources is much more common than atherothrombotic infarcts and is of a much greater concern.¹⁸²

Brain Embolism

One point against a hemodynamic or hypoperfusion cause of many strokes is their timing. It appears that strokes may occur more frequently after recovery from the anesthetic.^205,228,229 If the mechanism of stroke were hemodynamic, the major circulatory stress would be intraoperative and patients would at least awaken from anesthesia with the deficit. In two studies in which the authors record the timing of CABG surgery–related strokes, only 16%²²⁸ and 17%²²⁹ of patients had deficits noted immediately postoperatively. The distribution of infarcts and their multiplicity on neuroimaging scans were most consistent with embolism. Embolic infarcts may involve either the anterior or the posterior circulation.^{182,213,227,228} In one series of postoperative, posterior circulation strokes, most were embolic and followed cardiac surgery.²²⁹

In cardiac surgery patients, the preponderance of evidence suggests that macroemboli (> 200 μm in diameter) and microemboli are responsible for most neurologic complications.^{207,213,220,230,231} Macroemboli (associated with atherosclerotic plaque disruption or rupture) are believed to precipitate focal deficits, whereas particulate microemboli (white blood cell and platelet aggregates, fat, or air) may be implicated in more subtle diffuse cognitive dysfunction.^207,232

Emboli may arise from preexisting cardiac abnormalities (such as hypofunctioning ventricles, dilated atria, and aortic atheromas) or from postoperative arrhythmias.¹⁷² Evidence links operative and postoperative embolism to aortic ulcerative atherosclerotic lesions. Cross-clamping of the ascending aorta and aortotomy liberate cholesterol or calcific plaque debris.^182,233 Data from a series of 2641 consecutive cardiac surgery patients showed that left-body symptoms (right hemispheric stroke) were twice as common as right-body symptoms, suggesting that aortic manipulation and anatomic mechanisms in the aortic arch were more likely to cause cerebrovascular accidents than effects from aortic cannula stream jets.²³⁴ Figure 94–1 shows the aorta of a patient who died having never awakened after CABG. Figure 94–2 shows cholesterol crystals and other debris trapped within a filter placed in the aorta at the time of unclamping.

Given that atherosclerosis of the ascending aorta is a significant risk for perioperative stroke,²³⁵ it was postulated that avoiding direct manipulation of this area may improve neurologic outcome postoperatively. Epiaortic ultrasound scanning is thought to be superior to both manual palpation of the ascending aorta and TEE in detecting atherosclerosis, particularly noncalcified plaque. It has led to modifications in surgical management in patients undergoing CABG, such as modification of cannulation, clamping, or anastomotic technique, and temperature management.^236,237,238 One study suggested that the application of aortic clamping or cardiopulmonary bypass was not a risk when the ascending aorta was evaluated using epiaortic ultrasound.²³⁶ A second study of 6051 patients also noted that the overall stroke risk was lower in patients who had intraoperative epiaortic ultrasound, compared with all patients undergoing cardiac surgical procedures.²³⁹ Why the stroke risk is lower is not yet clear; a separate study found that the use of this imaging technique did not lead to a reduced number of TCD ultrasound–detected cerebral microemboli before or during bypass.²³⁷ One might theorize that this technique reduces macroemboli and not microemboli.

In another series in which embolic signals were monitored during CABG surgery, 34% of signals were detected as the aortic cross clamps were removed, and another 24% were detected as aortic partial occlusion clamps were removed.²³³ The number of microemboli detected correlated with abnormalities of cognitive function after surgery.^182,240 Figure 94–3 shows microemboli within the aorta shown by TEE after release of aortic clamps. Figures 94–4 and 94–5 are TCD recordings during manipulation of the aorta and after release of aortic clamps.

In a similar study within a Chinese population of 227 patients, off-pump CABG surgery was noted to significantly decrease the number of cerebral microembolic events detected by TCD. This also could be explained by the aortic clamping technique required for traditional CABG. Interestingly, though, this study also found that the incidence of postoperative cognitive dysfunction was not decreased by off-pump CABG, which suggests that microemboli may not be the responsible culprit for this phenomenon.²⁴¹

Thromboembolic infarction often occurs in the days following surgery when cessation of anticoagulation is necessary. Postoperative activation of coagulation factors in cardiac surgery patients can promote hypercoagulability. Disseminated intravascular coagulation, acquired antithrombin III deficiency, and acquired protein C deficiencies are not uncommon. Activation of the coagulation-fibrinolytic system can persist for 2 months after cardiopulmonary bypass surgery.^242,243 In some patients, hypercoagulability related to surgery can precipitate occlusive thrombosis in atherostenotic arteries, and the newly formed thrombus can lead to intra-arterial embolism. Cardiac, aortic, and intra-arterial embolism accounts for the vast majority of cardiac surgery–related focal neurologic deficits.

With regard to interventional treatment of cardiac surgery patients with an acute embolic stroke, unfortunately, given their recent surgery, these patients are not candidates to receive intravenous tissue plasminogen activator (t-PA). However, these patients may still be candidates for endovascular acute stroke treatment. The MR CLEAN trial recently demonstrated that patients with acute ischemic stroke caused by intracranial large vessel occlusion clearly benefit from intra-arterial therapy.²⁴⁴ In this trial, intra-arterial therapy consisted of intra-arterial thrombolysis with alteplase or urokinase, mechanical treatment or both. Mechanical treatment refers to retraction, aspiration, sonolysis, or use of a retrievable stent (stent-retriever). Several other positive trial results confirmed these findings at the International Stroke Conference in 2015.

There was still uncertainty about the effect of intra-arterial therapy in patients with contraindications for treatment with intravenous alteplase treatment (such as the cardiac surgery population). A recent 2016 MR CLEAN subgroup analysis demonstrated that in those patients with acute ischemic anterior circulation stroke caused by intracranial large vessel occlusion, who have contraindications for intravenous alteplase, intra-arterial treatment is not less effective or less safe than in patients who receive the treatment after intravenous alteplase.²⁴⁵

Postoperative Encephalopathy: Microemboli and Other Causes

Gilman²⁴⁶ described a diffuse CNS disorder following open heart surgery (characterized by altered levels of consciousness and activity and confusion) that is now referred to as encephalopathy. Clinical and imaging studies usually do not show important focal neurologic signs or large focal infarcts. The incidence of encephalopathy varies. In one series, 57 (3.4%) of 1669 CABG patients had postoperative mental state changes including delirium and encephalopathy.²⁴⁷ In the Cleveland Clinic prospective series, 11.6% of patients were encephalopathic on the fourth postoperative day.²⁰⁰ Additionally, the incidence of encephalopathy also varies depending on the cardiac procedure itself. Compared with conventional on-pump CABG, off-pump CABG has been shown to reduce postoperative neuropsychological dysfunction in elderly patients with severe systemic atherosclerosis.²⁴⁸

Encephalopathy has multiple causes. A necropsy study of patients who died after cardiopulmonary bypass or angiography has awakened interest in this subject.²⁴⁹ Focal, small capillary and arteriolar dilatations (SCADs) were commonly found in the brain.²⁴⁹ Approximately one-half of the SCADs show birefringent crystalline material within the dilated capillaries. SCADs could, at least in part, explain the decreased cerebral blood flow found during cardiopulmonary bypass. SCADs are iatrogenically generated microemboli, but as yet, their origin is unknown. Their morphology is most consistent with air or fat.²⁴⁹

Other causes of encephalopathy are common. Diffuse hypoxic-ischemic insults from hypotension and hypoperfusion do occur. Postoperative cognitive dysfunction at 1 week after surgery has been associated with increasing age and shorter duration of hospital stay.²⁴¹ Cognitive dysfunction at 3 months after CABG has also been associated with increasing age and with diabetes mellitus.²⁴¹ Lastly, drugs are a common cause of encephalopathy in the postoperative period. Particularly important are haloperidol, narcotics, and sedatives. Morphine is sometimes used heavily intraoperatively, and opiate withdrawal with restlessness and hyperactivity can result. Agitation and restlessness are often early signs of organic encephalopathy and may lead to the administration of haloperidol, barbiturates, phenothiazines, or benzodiazepines for calming and sedation. When these drugs wear off and the patient begins to awaken, agitation may occur, and more sedatives may be given. Haloperidol causes rigidity, restlessness, agitation, hallucinations, and confusion. In experimental animals, haloperidol delays recovery from strokes by months, and its use is not advised.^250,251 Phenothiazines and sedatives are also problematic; in general, use of sedatives and narcotics should be minimized, and they should be tapered as soon as possible.

Postoperative Intracranial Hemorrhage

Intracerebral or subarachnoid hemorrhages have occasionally been reported after cardiac surgery, most commonly in children who had repair of congenital heart disease²⁵² or in cardiac transplantation patients.²⁵³ The postulated mechanism involves an abrupt increase in brain blood flow with rupture of small intracranial arteries unprepared for the new load. Usually, there is a prolonged period when cardiac output is low, and this output is suddenly increased by the surgery. Abrupt increases in brain blood flow or pressure in other situations have also been associated with ICH.²⁵⁴

Stroke Mimics: Postoperative Peripheral Nerve Complications

Brachial plexus and peripheral nerve lesions frequently develop after cardiac surgery and can be confused with CNS complications.²⁵⁵ In one series, new peripheral nervous system deficits occurred in 13% of patients.²⁵⁵ The most common deficit is a unilateral brachial plexopathy characterized by shoulder pain and usually weakness and numbness of one hand. It is probably caused by either sternal retraction or positioning of the arm during surgery, with traction on the lower trunk of the brachial plexus. Ulnar, peroneal, and saphenous nerve injuries are also common and are also related to positioning. Diaphragmatic and vocal cord paralyses are likely related to local effects of the cardiac surgery on the recurrent laryngeal and phrenic nerves. Postoperative Horner syndrome may be caused by manipulation of the sympathetic chain, but carotid dissection (particularly in surgical patients undergoing aortic dissection repair) should be excluded.

Information is beginning to emerge on cardiac muscle changes (myocytolysis), arrhythmias, pulmonary edema, ECG changes, and sudden death caused by brain disease and sudden emotional stresses.^256,257

Cardiac Lesions

The two most common lesions found in the hearts of patients dying with acute CNS lesions are patchy regions of myocardial necrosis and subendocardial hemorrhage. The abnormalities range from eosinophilic staining of cells with preserved striations to transformation of myocardial cells into dense eosinophilic contraction bands. These changes have been referred to as myocytolysis.^256,257 One study found a high incidence of myocardial abnormalities in patients dying of brain lesions that increase intracranial pressure rapidly.²⁵⁸ Stress-related release of catecholamines and possibly corticosteroids may be responsible, in part, for the cardiac lesions found in patients with CNS lesions.^{256,259,260,261,262,263,264} Adrenoreceptor polymorphisms can explain increased catecholamine sensitivity and thus increased risk of cardiac injury in patients with subarachnoid hemorrhage (SAH) and acute ischemic stroke.²⁶⁵

Electrocardiographic and Enzyme Changes

In stroke patients, especially those with SAH, ECGs may show a prolonged QT interval; giant, wide, roller coaster–inverted T waves; and U waves.²⁶⁶ These changes are often called cerebral T waves. Patients with stroke undergoing continuous ECG monitoring have a high incidence of T-wave and ST-segment changes, various arrhythmias, and cardiac enzyme abnormalities. ECG changes may include a prolonged QT interval, depressed ST segments, flat or inverted T waves, and U waves.^{256,266,267,268,269} Less often, tall, peaked T waves and elevated ST segments are noted. Myocardial enzyme release and echocardiographic regional wall motion abnormalities are associated with impaired LV performance after SAH. In severely affected patients, reduction of cardiac output may elevate the risk of vasospasm-induced cerebral ischemia.²⁷⁰ Cardiac and skeletal muscle enzymes, including the MB isoenzyme of creatine kinase (CK-MB), are often abnormal in stroke patients.^{269,271,272,273,274} During days 4 to 7 after stroke, there is usually a slow increase and later decrease in serum CK-MB levels, a pattern quite different from that found in acute MI; the temporal pattern of cardiac isoenzyme release is more compatible with smoldering low-grade necrosis, such as patchy, focal myocytolysis.^275,271 The ST-segment and T-wave abnormalities and cardiac arrhythmias correlate significantly with increased levels of CK-MB in stroke patients.²⁷⁵

Arrhythmias

Various cardiac arrhythmias have been found in stroke patients, most frequently sinus bradycardia and tachycardia and premature ventricular contractions.^{256,267,268,269} Some arrhythmias are manifestations of primary cardiac problems, but others are undoubtedly secondary to the brain lesions. The incidence of sinus tachycardia and bradycardia is maximal on the first day after ICH.²⁷⁴ Ventricular bigeminy, atrioventricular dissociation and block, ventricular tachycardia, AF, and bundle-branch blocks are found less often.²⁷⁶ Arrhythmias are more common in patients who have primary brainstem lesions or brainstem compression.

Echocardiographic Changes

Takotsubo cardiomyopathy is also known as broken heart syndrome, as well as transient LV apical ballooning. The name takotsubo cardiomyopathy was initially coined because the shape of the end-systolic left ventriculogram was thought to resemble an octopus catcher used in Japan.^277,278 It has been found after severe emotional stress, especially in postmenopausal women, and has been identified in both SAH and ischemic stroke patients.^277,279 In ischemic stroke patients, it occurs soon after stroke onset, is commonly asymptomatic, and is associated with insular damage.²⁸⁰

Echocardiography can show a hyperkinetic basal region and an akinetic apical half of the ventricle, traditionally in the setting of minimal cardiac enzyme release and normal coronary arteries on angiography. However, there are actually multiple patterns of takotsubo.^277,278,279

Stimulation of the limbic system, including the insula, can result in marked sympathetic activation.²⁸¹ With this unifying pathophysiology of excessive sympathetic discharge, the broken heart syndrome may represent a variant of the regional wall motion abnormality phenomenon associated with SAH.²⁸² Prognosis is generally very good, with full recovery in most patients; however, there may be increased morbidity in patients with SAH.²⁸² Thus, it may be reasonable to consider TTE in SAH patients with ECG abnormalities.²⁸²

Neurogenic Pulmonary Edema

Acute pulmonary edema may complicate strokes, especially SAH, subdural hemorrhage, primary spinal cord hemorrhage, and posterior circulation ischemia and/or hemorrhage.^{275,283,284,285} Pulmonary edema has been found in 70% of patients with fatal SAH and correlates with the development of increased intracranial pressure.²⁸⁶ The pulmonary edema can develop despite normal cardiac function.^275,287 The most relevant imaging method is the chest x-ray, where diffuse hyperintensive infiltrates in both lungs are apparent. Although the levels of some substances such as brain natriuretic peptide, blood C-reactive protein, and interleukin-6 are increased, unfortunately, none of these tests is a specific marker for neurogenic pulmonary edema.^284,285

Sudden Death

Sudden death associated with stressful situations, including so-called voodoo death, must involve CNS mechanisms.^{264,288,289,290,291,292,293} However, the role that the CNS plays in precipitating sudden cardiac death is still uncertain. In particular, establishing a cause-effect relationship in the setting of a stroke has been complicated because these patients usually have risk factors for coronary disease as well.²⁹⁴ However, it is notable that patients with lateral medullary and lateral pontine infarcts die unexpectedly and also have a high incidence of autonomic dysregulation (eg, labile blood pressure, tachycardia).

ECG alterations predictive of sudden death, such as QT prolongation, late ventricular potentials, premature ventricular beats, nonsustained ventricular tachycardia, and the R on T phenomenon, have been described in patients with SAH, ICH, and ischemic stroke. Additionally, a higher incidence of ventricular arrhythmias, particularly ventricular fibrillation (the presumed mechanism of sudden death), has been noted in acute stroke patients.^294,295,296 Ventricular fibrillation can be reliably elicited by stimulation of cardiac sympathetic nerves in both the normal and the ischemic heart.²⁹² Postmortem analysis of patients who died suddenly and without any evidence of coronary disease often shows myocytolysis and myofibrillar degeneration (which is observed also in experimental models of hearts subjected to sympathetic overstimulation).^294,297 Sudden vagotonic stimulation can cause bradycardia and cardiac standstill; however, the effects of vagal stimulation on the development of ventricular arrhythmias are uncertain.²⁹²

Atherosclerosis

The most common and important vascular disease that affects both the brain and the heart is atherosclerosis. The most frequent cause of death in stroke patients is coronary artery disease,²⁹⁰ and extra- and intracranial arterial atherosclerosis is common in patients with coronary artery disease.²⁹¹

Pathology and Predominant Sites of Disease

In white men, the predominant atherosclerotic lesions involve the origins of the internal carotid artery (ICA) and the vertebral artery (VA) origins in the neck.^{45,298,299,300} Fatty streaks and flat plaques first affect the posterior wall of the common carotid artery (CCA).^301,302 Atherosclerotic plaques at this site do not differ from plaques in the aorta or coronary arteries. At first, plaques expand gradually and encroach on the lumen of the ICA and sometimes the CCA. Atheromatous plaques often develop concurrently at the VA origin or spread from the parent subclavian artery to involve the VA origin.^44,303 When plaques reach a critical size, they affect turbulence, flow, and motion of the arteries, causing complications to develop within the plaques. Cracking, ulcerations, and mural thrombi develop, and the overlying endothelium is damaged with the development of occlusive thrombi.³⁰⁴ Fresh thrombi loosely adherent to vascular walls rapidly propagate and embolize. Because the ICA has no nuchal branches, the clot often propagates cranially. In the initial 2 to 3 weeks after the development of an occlusive thrombus, the clot gradually organizes and is much less likely to propagate or embolize. The reduction in cranial blood flow caused by severe stenosis or occlusion of the ICA or VA stimulates development of collateral circulation that usually becomes adequate.

Figure 94–6 shows diagrammatically the sites of predilection for development of atherosclerosis in the cervicocranial circulation. Note the concentration of these sites at branch points and flow dividers. There are important race and sex differences in the distribution of cerebral atherosclerosis.^{305,306,307,308} White men usually develop lesions of the ICA and VA origins. Patients with ICA-origin disease have a high frequency of hypercholesterolemia, coronary artery disease, and peripheral vascular occlusive disease. Blacks and individuals of Chinese, Japanese, and Thai ancestry have a much higher incidence of intracranial occlusive disease and a rather low frequency of extracranial disease.^{305,306,307,308,309} Intracranial disease is more prevalent in women and diabetics. Interestingly, patients with intracranial occlusive disease do not have a high incidence of coronary or peripheral vascular occlusive disease.

Mechanisms of Ischemia

Ischemia in patients with atherosclerotic occlusive lesions is caused by two different mechanisms: hypoperfusion and embolism.^45,310,311 Hypoperfusion develops only when a critical reduction in luminal diameter causes reduced distal perfusion. When flow is reduced slowly, the brain vasculature has a remarkable capacity to develop collateral circulation. Patients with severe ICA-origin occlusive disease can remain asymptomatic despite marked decrease in blood flow.^312,313 Even when vascular occlusion is abrupt—as in tying neck arteries to treat brain aneurysms—surprisingly few patients develop persistent brain ischemia. In most patients, within a few days or at most 2 weeks following an arterial occlusion, collateral circulation stabilizes.

Intra-arterial embolism from atherosclerotic lesions is probably a much more frequent and important cause of brain infarction than hypoperfusion. However, decreased perfusion probably limits clearance (washout) of emboli.³¹¹ In patients with anterior circulation infarcts, angiography shows a very high frequency of intra-arterial intracranial emboli distal to an ICA thrombosis.³¹⁴ These emboli most often involve the MCA and its branches. If angiography is repeated or performed later than 48 hours after stroke, MCA occlusion is usually not present.^29,45 Intra-arterial emboli often fragment and move distally. Intra-arterial embolism is also common in the posterior circulation, where the most common donor sites are the VA origin and intracranial VA.³¹⁵

Clinical Findings

Many patients with atherosclerotic occlusive disease are asymptomatic. The most frequent symptoms of hypoperfusion or embolism are headache, TIAs, and focal neurologic signs from brain infarction. Headaches are caused by vascular distension or brain swelling secondary to infarction. Unaccustomed headaches often precede strokes.^45,316 TIAs are caused by hypoperfusion or intra-arterial emboli. Frequent, very brief stereotyped TIAs precipitated by postural changes, also known as limb-shaking TIA, can suggest a hemodynamic mechanism. In contrast, emboli cause longer, less frequent attacks.^310,317 In many patients with clinical TIAs (spells < 24 hours in duration with no lasting symptoms or signs), neuroimaging tests show brain infarcts.^318,319

Neurologic symptoms and signs depend on the region of brain that is ischemic. Table 94–2 outlines the most frequent clinical patterns resulting from occlusions of the major extracranial and intracranial arteries.^45,300

Diagnostic Testing

In most patients, the nature and severity of the brain and vascular lesions causing the stroke can be defined. CT and MRI should localize brain lesions, distinguish between infarcts and hemorrhages, and determine the location, extent, and size of the processes. CT or MRI is usually the first test in patients with suspected stroke because the information allows clinicians to exclude nonvascular disease such as tumor or abscess, differentiate hemorrhage from ischemia, identify the vascular territory involved, and define the extent of brain damaged.

The vascular territory involved should be inferred by the nature of the neurologic symptoms and signs and the location of brain lesions on CT or MRI. Echocardiography, especially TEE, has dramatically improved the ability to detect potential cardiac sources of emboli. Ultrasound techniques can be used to screen for obstructive lesions in the major extracranial and intracranial arteries in both anterior (carotid) and posterior (vertebrobasilar) circulation arteries. For extracranial use, the two most important are B-mode scans and Doppler spectra, both pulsed and continuous-wave (CW) Doppler. The anatomy of the carotid bifurcation (the CCA, proximal ICA, and external carotid artery) and the proximal VAs can be imaged by high-frequency, 5- to 10-MHz, B-mode ultrasound systems, which provide images of the vessels in real time both longitudinally and in cross-section (Fig. 94–7). Plaque calcifications and clot are often difficult to image. Pulsed Doppler registers frequency shifts from moving columns of blood. Doppler analysis can show the direction and velocity of blood flow. Multigated Doppler and B-mode scanning are now used together in so-called duplex systems.^45,320,321 The duplex system is probably > 90% effective in differentiating arteries that are normal or minimally narrowed from those that have moderate disease (30%-70% narrowing) and from those with severe narrowing (> 70% stenosis). B-mode scanning sometimes suggests the presence of ulceration or hemorrhage in plaques that show heterogeneous images.³²¹ CW Doppler uses a movable probe to measure flow velocities along the carotid and vertebral arteries; the technique is less time consuming and less expensive than the duplex system and, in expert hands, is very accurate in detecting high-grade stenosis.^321,322 Ultrasound techniques cannot reliably separate complete occlusion from very high degrees of stenosis. Color flow and power Doppler can show turbulence and altered flow dynamics.

TCD ultrasound is used to analyze the presence of intracranial arterial stenoses and provide information about the intracranial effects of extracranial occlusive lesions. The technique takes advantage of the soft spots in the temporal bones and natural foramina (the orbit and foramen magnum) that provide windows for ultrasound recording. The depth and angle of the probe recording can be varied, allowing the recording of velocities and sound spectra from all the major intracranial arteries.^45,140,323 Major obstructive lesions are reliably shown by both extracranial ultrasound and TCD. Continuous recording of intracranial arteries with TCD is a very sensitive and accurate method of detecting microemboli passing under the probes.^{182,233,324,325} Examples of microembolic signals are shown in Figs. 94–4 and 94–5.

MRA provides an additional method of imaging both the extracranial and intracranial arteries for areas of stenosis and occlusion.^326,327 CTA, using a spiral (helical) CT machine and dye injected intravenously, can also image the major large craniocervical arteries.³²⁷ Standard catheter angiography is warranted when ultrasound and CTA or MRA have not sufficiently defined the vascular lesion and treatment is clinically feasible.^45,309

Treatment

For rational treatment, know the following:

• Location, nature, and severity of the occlusive lesion

• Location, extent, and reversibility of the brain lesion

• Blood constituents and coagulability^45,328

Treatment should not be guided solely by the temporal pattern of the symptoms, such as TIA, progressing stroke, or so-called completed stroke.^{45,318,328,329} These time courses do not predict the cause and mechanism of ischemia, identify whether an infarct is present, or identify patients who will have further or recurrent ischemia.³²⁹

Physicians should first decide whether or not any specific therapy is indicated. Very severe neurologic deficits, serious intercurrent illnesses (eg, dementia, cancer), and psychosocioeconomic considerations may make patients unsuitable for specific treatments. If treatment is feasible, two questions should be considered next: What brain tissue is at risk for further ischemia? What is the benefit-to-risk ratio of specific treatments? To determine the tissue at risk, clinicians consider the cause and the deficit. For example, a man with a slight hemiplegia caused by a small lacunar infarct in the anterior limb of the internal capsule may have infarcted the entire tissue supplied by an occluded small artery. In that case, treatment consists of controlling hypertension, the cause of the microvasculopathy. If, however, that same patient has a small cortical infarct in the precentral gyrus caused by ICA disease, the rest of the ICA territory is at risk for further ischemia, and aggressive treatment is warranted. Newer MRI techniques, such as diffusion-weighted and perfusion MRI, along with MRA, can show, even very soon after symptoms begin, brain tissue that is already infarcted and brain tissue that is underperfused but not yet infarcted.^{45,327,330,331}

Patients who have little tissue at risk are not candidates for specific interventional therapy. If there is considerable residual at-risk tissue, the guidelines in Table 94–3 are used to direct treatment, which depends on the location and severity of the causative vascular lesions. CEA is effective in symptomatic patients with severe ICA stenosis (> 70%). For patients with carotid stenosis < 50%, these trials showed there was no significant benefit from CEA. For those with carotid stenosis in the moderate category (50%-69%), the relative and absolute risk reductions were less impressive than for those in the severely stenotic group.^{332,333,334,335}

The Asymptomatic Carotid Artery Study (ACAS) suggested that CEA is slightly better than medical therapy in asymptomatic patients with severe carotid stenosis when the operation is executed by surgeons who have records of very low surgical morbidity and mortality.³³⁶ To be effective, the operative mortality and morbidity of CEA must be ≥ 2% to 4%.^{332,333,334,335,336} Surgery is also feasible on the extracranial VA in selected patients with intra-arterial embolism from this site or with intractable posterior circulation hemodynamic ischemia, which is a rare occurrence.³³⁷

Data on carotid (artery balloon) angioplasty and stenting (CAS) is emerging. The Wallstent Trial randomized 219 symptomatic patients with 60% to 90% stenosis to either CEA or CAS. In this early study, CAS was performed without distal protection and without antiplatelet prophylaxis, and the study design also allowed operators with limited experience to participate. The risk of perioperative stroke or death was 4.5% for CEA and 12.1% for CAS; 1-year risk of major stroke and death was 0.9% for CEA and 3.7% for CAS. The Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS), which compared CAS with CEA, did not find a difference in the rate of ipsilateral ischemic stroke up to 3 years after randomization. Several randomized comparisons of CAS versus CEA have helped to clarify the relative benefits and risks of these two procedures. Differences in the inclusion criteria of these three studies, use of embolic protection devices, and operator experience all need to be considered in interpreting their results.²⁹⁴

1. The Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial randomized 334 patients to CAS or CEA. Distal protection devices were used, and study operators had a periprocedural stroke, death, or MI complication rate of ≤ 4%. Thirty percent of the study population was symptomatic with a stenosis > 50%. The remainder (and the majority of) the study’s patients had an asymptomatic carotid stenosis > 80%. Results revealed that CAS did not appear to be inferior to CEA, with a benefit of lower MI risk being detected in the CAS group.^{8,338,339,340} In the 3-year follow-up from the SAPPHIRE trial published in 2008, 15 patients in both treatment groups had experienced stroke, for an estimated stroke rate of 2.3% per year.³⁴¹

2. The Stent-supported Percutaneous Angioplasty of the Carotid Artery Versus Endarterectomy (SPACE) trial assessed 1200 symptomatic patients with ipsilateral carotid stenosis > 50% and a history of stroke or TIA. The average degree of stenosis in this study was between 80% and 89%. Ipsilateral ischemic stroke and death within 30 days were the primary outcomes observed and were found to be roughly equal. Rates of stroke and death 2 years after treatment were also similar. Multiple types of cerebral protection devices and stents were used.³⁴²

3. The Endarterectomy Versus Angioplasty in Symptomatic Severe Carotid Stenosis (EVA-3S) study followed 520 symptomatic patients with a prior ischemic stroke or TIA as well as a carotid stenosis of > 60%. The average degree of stenosis was similar to that in the SPACE trial at approximately 85%. Primary outcome was stroke or death within 30 days of randomization. This trial was stopped early because of futility and safety concerns; a higher risk of stroke was seen early in the trial with CAS when distal protection devices were not used, and the protocol was amended to recommend their use. The risk of stroke or death at 30 days was significantly lower in the CEA group (4%) than the CAS group (10%) and thought, in part, to reflect the issues with distal cerebral protection in the CAS group and operator inexperience at certain sites.³⁴³

4. The CREST study (Carotid Revascularization Endarterectomy versus Stenting Trial), which followed 2502 patients, initially found no significant difference between the stenting group and the endarterectomy group with respect to the primary composite end point of stroke, MI, or death during the periprocedural period or any subsequent ipsilateral stroke during 4 years of follow-up. Those results now extend to 10 years. With respect to the primary long-term end point, postprocedural ipsilateral stroke over the 10-year follow-up occurred in 6.9% of the patients in the stenting group and in 5.6% of those in the endarterectomy group; the rates did not differ significantly between the groups. No significant between-group differences with respect to either end point were detected when symptomatic patients and asymptomatic patients were analyzed separately. Over 10 years of follow-up, the investigators did not find a significant difference between patients who underwent stenting and those who underwent endarterectomy with respect to the risk of periprocedural stroke, MI, or death and subsequent ipsilateral stroke. The rate of postprocedural ipsilateral stroke also did not differ between groups.³⁴⁴

A consistent finding in the first three trials listed above was that after the first 30 days, the long-term ipsilateral stroke rate was < 1% per year with either procedure.²⁹⁴ Despite these trials, there is still much debate regarding the optimal role of CAS versus CEA in stroke prevention. However, a recent large sample of US hospitals, identifying a total of 121,157 CEA and 18,503 CAS procedures performed at 445 medical centers, demonstrated that performance of CAS significantly increased after the publication of the CREST study.³⁴⁵

With regard to medical therapy, for minor and moderate degrees of stenosis in extra- and intracranial arteries, agents that alter platelet aggregation and adhesion are recommended. The most likely mechanism of ischemia in these patients is white clot, or platelet fibrin emboli. Aspirin,³⁴⁶ ticlopidine,³⁴⁷ clopidogrel,³⁴⁸ and Aggrenox (a tablet containing aspirin 25 mg and modified-release dipyridamole 200 mg given two times a day)³⁴⁹ have all proven effective in randomized trials in preventing a recurrent stroke after an initial noncardioembolic stroke. There is debate about which individual or antiplatelet therapy should be selected. The results of the Management of Atherothrombosis With Clopidogrel in High-Risk Patients with TIA or Stroke (MATCH) trial assessed patients with a prior stroke or TIA (n = 7599) who were assigned to either clopidogrel 75 mg daily or combination therapy (clopidogrel 75 mg daily plus aspirin 75 mg daily). Primary outcomes observed included ischemic stroke, MI, vascular death, and rehospitalization caused by ischemic event. There was no significant benefit observed in the combination group compared with clopidogrel alone; the risk of major hemorrhage was also increased in the combination therapy group. Thus, although clopidogrel plus aspirin is recommended over aspirin alone for acute coronary syndromes, the MATCH results do not suggest a similar benefit for stroke and TIA patients.^18,350 Clopidogrel is as effective as ticlopidine and has fewer serious hematologic complications.³⁴⁸

The Prevention Regimen for Effectively Avoiding Second Strokes (PROFESS) trial compared the efficacy and safety of aspirin plus extended-release dipyridamole with the efficacy and safety of clopidogrel among patients who had experienced a recent noncardioembolic ischemic stroke. Treatment with the combination therapy was associated with a reduction of 25 ischemic strokes compared with clopidogrel but with an increase of 38 hemorrhagic strokes and four strokes of unknown etiology. Despite the increase in bleeds, when stroke recurrence and major hemorrhage were combined into one end point reflecting a benefit-risk relationship, no statistical difference between the two groups was noted. So which drug should a physician choose while we are waiting for guideline committees to review the data and make a formal recommendation? There is a range of reasonable conclusions, and the decision should depend on factors such as adverse effects (eg, headache with the combination drug), medical history (eg, angina or stenting, which may warrant clopidogrel), and cost. All factors being equal, our personal preference is clopidogrel.³⁵¹

For patients with severe stenosis of large intracranial arteries, we previously recommended warfarin if there were no contraindications. The randomized, double-blind, multicenter Warfarin-Aspirin Recurrent Stroke Study (WARSS) compared the efficacy of aspirin with warfarin (INR 1.4-2.8) for the prevention of secondary ischemic stroke caused by noncardioembolic sources (n = 2206). Various subgroups, including large-artery atherosclerotic lesions, were evaluated. No significant differences between aspirin and warfarin for secondary stroke prevention or death were found. However, patients treated with warfarin in whom the INRs were in the target range had significantly fewer strokes than patients treated with aspirin. Given the cost of monitoring warfarin and the potential increase in bleeding risk with warfarin use, the authors recommended that antiplatelets be chosen over anticoagulants for stroke prevention in patients with prior noncardioembolic strokes.^8,352 This study predated introduction of NOACS.

The state of the intracranial arteries can be monitored using TCD and/or MRA or CTA.³²⁷ For patients with complete occlusions and with stump emboli–induced ischemic strokes, we still recommend heparin and then warfarin for 2 to 3 months.⁴⁵ Heparin should be used without a bolus, and target INR with warfarin should be 2.0 to 3.0.

Thrombolytic drugs, especially recombinant tissue-type plasminogen activator (rt-PA) and streptokinase, have been given intravenously and intra-arterially in patients with acute brain ischemia. In a study in which the arterial lesions were undefined, intravenous therapy with rt-PA given within 90 minutes and 3 hours of ischemia onset, in the aggregate, provided a statistically significant benefit.³⁵³ Additionally, in a more recent study, intravenous t-PA was found to be of overall benefit even when given 3 to 4.5 hours after ischemic stroke symptom onset.³⁵⁴ Unfortunately, in these and other studies, approximately 6% to 12% of patients treated with thrombolytic agents developed important intracranial bleeding. Uncontrolled studies show that patients with distal intracranial arterial embolic occlusions do well with intravenous thrombolytic therapy.^{355,356,357,358,359,360} Patients with ICA occlusions in the neck and intracranially rarely reperfuse after intravenous thrombolytic therapy, especially if collateral circulation is poor. Intra-arterially administered prourokinase thrombolysis has also been proven to be very effective in opening blocked intracranial arteries within the anterior circulation.³⁶¹ The dose, timing, mode of delivery, and target group for therapy remain unsettled. The authors believe vascular imaging should precede administration of thrombolytic agents. Brain and vascular imaging can guide physicians as to who should receive thrombolytics and by what route.³⁶²

Because all patients with atherosclerosis are at risk of developing more lesions, control of risk factors is very important and should be begun in the hospital. Risk factors include smoking, hyperlipidemia, obesity, inactivity, and hypertension. Blood pressure should not be excessively lowered during the acute ischemic period because this may decrease flow in collateral arteries. Blood pressure control can be instituted 3 to 4 weeks after the stroke. Rehabilitation must also begin early.

Management of Coexisting Coronary and Cerebrovascular Disease

In patients considered for cardiac surgery who have symptoms of brain ischemia, it is important to define the extent of cerebrovascular disease preoperatively by noninvasive means (ultrasound and/or MRA), as well as to define cardiac and coronary artery anatomy and function. In some patients with excessive surgical risks, anticoagulation may represent an alternative treatment. Clearly, optimal medical therapy should be instituted preoperatively and continued after surgery.

Systemic Arterial Hypertension

High blood pressure, both acute and chronic, damages deep, penetrating small intracranial arteries; accelerates the development of atherosclerosis in the extracranial and large intracranial arteries; and results in ischemic syndromes of lacunar infarction,^45,360,361 diffuse ischemic changes in white matter and basal gray matter structures (Binswanger disease^45,362), and ICH. Hypertension is also frequent in patients with aneurysmal SAH and may contribute to enlargement and rupture of aneurysms.

Hypertension especially damages the deep arteries that penetrate perpendicularly from the major intracranial arteries (Fig. 94–8).

The two major patterns of brain ischemia in patients with hypertension are discrete lacunar infarcts and a more diffuse, patchy, white and gray matter degeneration with gliosis. Both are caused by sclerotic changes in deep intracerebral arteries and arterioles. The term lacune (hole) refers to a small, deep infarct caused by lipohyalinosis of the penetrating artery feeding the ischemic brain tissue.^363,364 Amyloid angiopathy can also cause small, deep infarcts in normotensive and hypertensive patients. Single lacunes cause discrete clinical syndromes.^45,365 The most common syndromes are pure motor hemiparesis,³⁶⁶ pure sensory stroke,³⁶⁷ ataxic hemiparesis,³⁶⁸ and the dysarthria–clumsy hand syndrome.³⁶⁹

Since the advent of CT and MRI, it has become widely appreciated that hypertensive patients with lacunes often have more diffuse changes in the white matter of the brain, referred to as leukoariosis.^362,370 The clinical picture consists of acute strokes; subacute progression of neurologic signs; dementia; slow shuffling gait disorder; and parkinsonian, pyramidal, and pseudobulbar signs.^362,371,372 The clinical signs and gross pathology are identical to those partially described by Otto Binswanger in 1894 and 1895³⁷¹ and by his students Alzheimer and Nissl.³⁷¹ The deep arteries are thickened and hyalinized and show lipohyalinosis and sometimes amyloid angiopathy in regions of white matter atrophy and gliosis. Invariably, lacunar infarcts are also found. The diagnosis is made based on the clinical findings, the CT and MRI abnormalities, and the absence of cortical infarcts, larger artery occlusive disease, or cardioembolic sources.

Hypertensive Intracerebral Hemorrhage

ICH accounts for approximately 10% of all strokes.^29,45 Head trauma, vascular malformations, bleeding diatheses, drugs (especially anticoagulants, amphetamines, and cocaine), amyloid angiopathy, and intracranial aneurysms account for some cases.^326,342 Traditionally, spontaneous ICH has usually been equated with hypertensive hemorrhage. Many patients, however, have no history of hypertension or associated changes of hypertensive vasculopathy at necropsy.^257,373,374 Acute elevations of blood pressure and/or blood flow to the brain (Table 94–4) can cause ICH by the sudden increase in blood pressure, causing vessel breakage.²⁵⁴

Hypertensive ICH issues from the deep penetrating arteries, so the locations parallel the distribution of these arteries. Hypertensive hematomas develop in the same sites as lacunes; the most frequent locations are the putamen/internal capsule (30%-40%), caudate nucleus (8%), lobar white matter (20%), thalamus (15%), pons (10%), and cerebellum (10%). In fatal hematomas, microaneurysms and lipohyalinosis are prevalent in penetrating arteries, but the hematomas obscure findings in the middle of the lesions.³⁷⁵ Arterioles or capillaries rupture in the center of the lesion, suddenly increasing local tissue pressure and leading to pressure on adjacent capillaries, which then rupture. As the hematoma gradually grows on its periphery (Fig. 94–9), local tissue pressure and finally intracranial pressure increase until the hematoma is contained. Alternatively, the pressure is decompressed by the lesion, emptying into the ventricular system or into the subarachnoid space on the brain surface.⁴⁵

Clinical Findings

Patients with ICH most often have a gradual evolution of neurologic signs. The first neurologic signs are related to the bleeding site (eg, left putaminal hematoma patients might first notice right arm weakness or numbness).³⁷⁶ As the hematoma grows, focal signs worsen. When and if the hematoma increases in size to increase intracranial pressure, headache, vomiting, and decreased levels of alertness develop.³⁷⁶ In the presence of small, restricted hemorrhages, headache is absent, and the patient remains alert. Headache is absent or not a very prominent symptom in more than half of patients with ICH. Loss of consciousness is a bad prognostic sign when present.

Diagnosis

Noncontrast CT, MR-GRE, and MR susceptibility imaging accurately show the location, size, and shape of acute ICHs.³⁷⁷ Routine MRI (without MR susceptibility or GRE sequences) in the patient with an acute hematoma is more difficult to interpret. MRI is superior to CT in imaging arteriovenous malformations and cavernous angiomas. Lumbar puncture is seldom warranted. Atypical location, absence of hypertension, and abnormal vascular echoes on MRI are indications for angiography.

Prognosis and Treatment

Coma, increased intracranial pressure, and large hematoma size (> 3 cm in one dimension on CT) all indicate a poor prognosis.³⁷⁸ Ordinarily, severe systemic hypertension is reduced, but not excessively. Patients with ICH can die from increased intracranial pressure. To perfuse the brain and maintain an arteriovenous pressure gradient, the systemic arterial pressure must increase. Overzealous reduction of systemic blood pressure can cause clinical deterioration. The patient’s state of alertness and neurologic signs should be carefully monitored, together with the blood pressure.

Recent hematomas in the cerebral lobes, cerebellum, and right putamen are sometimes drained surgically without leaving a major deficit, at times using stereotactic equipment with CT guidance. The indications for drainage are increased intracranial pressure and the presence of lesions that require removal (eg, tumor, arteriovenous malformations, aneurysm).³⁷⁸ When hematomas resolve, they leave a cavity disconnecting, but not destroying, the overlying cortex.

Small hematomas usually resolve well without specific therapy except blood pressure control, whereas massive hematomas usually kill or maim patients before they can be treated. Medium-sized hematomas (2-4 cm) that increase intracranial pressure and cause worsening signs or decreased consciousness while patients are under observation are indications for drainage if the hematoma is favorably located.

Subarachnoid Hemorrhage

SAH is not directly caused by hypertension in most cases, although an abrupt increase in blood pressure (eg, caused by cocaine or amphetamines) can sometimes lead to SAH, as can a bleeding diathesis, trauma, and amyloid angiopathy. The most frequent lesions causing SAH are abnormal vessels such as aneurysms and vascular malformations on or near the surface of the brain. SAH describes bleeding directly into the subarachnoid space with rapid dissemination into the cerebrospinal fluid (CSF) pathways. Usually blood is suddenly released under systemic arterial pressure, causing an abrupt increase in intracranial pressure and producing headache, vomiting, and interruption of conscious behavior and memory, at least temporarily.^45,379 In some patients, the jet and spread of blood cause neckache, backache, or sciatica instead of headache. Patients are usually agitated and restless or sleepy and have a stiff neck.

The most frequent cause of SAH is leakage from a berry aneurysm. Often there has been a past history of a warning leak or sentinel hemorrhage, presenting as a sudden-onset headache unusual for the patient that lasts days and prevents normal activities.^379,380 Aneurysms are usually located at bifurcations of major intracranial arteries. CT can often suggest the site of rupture if blood is pooled locally near a typical site.³⁸¹ Large aneurysms are occasionally visible on contrast-enhanced CT or MRI. CTA and MRA are useful tests for screening for aneurysms.³²⁷ Lumbar puncture is very important in the diagnosis of SAH.³⁸² The absence of blood in the CSF effectively excludes the diagnosis of SAH if the fluid is examined within 24 hours of the onset of the headache, but bleeds that are very small in volume or older than 72 hours can be missed. The CSF pressure, presence of xanthochromia, and quantification of the hemoglobin and bilirubin content of the CSF by spectrophotometry can help establish and date the bleeding and document increased intracranial pressure.³⁸³

The two most important neurologic complications of aneurysmal SAH are rebleeding and brain ischemia caused by vasoconstriction (so-called vasospasm). Once an aneurysm has ruptured, either a tiny cap of platelets and fibrin seals the point of rupture or continued bleeding leads to death. Lysis of the fibrin cap initiates rebleeding. Surgical clipping of the aneurysmal sac or obliteration of the aneurysm by endovascular use of balloons or other devices should be attempted before rebleeding occurs.

Vasoconstriction of arteries is thought to be caused by blood or blood products that bathe the adventitia of arteries.^{383,384,385,386} In the presence of a large accumulation of blood, there is a much higher incidence of arterial vasoconstriction and resultant brain ischemia and infarction. Delayed ischemia can also develop after surgery, as manipulation of vessels can precipitate vasoconstriction. The clinical findings in patients with vasoconstriction are often those of diffuse brain swelling, such as headache, decreased alertness, and confusion. When vasoconstriction is focal, the clinical findings are those of focal ischemia, such as hemiparesis, aphasia, hemianopia, and so on. Vasoconstriction usually has its onset 3 to 5 days after hemorrhage. The peak time for constriction is on days 5 to 9; vasoconstriction usually improves after the second week unless rebleeding occurs.³⁸⁷

Vasoconstriction is detected by angiography in 30% to 70% of patients with SAH, depending on the timing of the study.^383,384 TCD is effective in monitoring for the presence of vasoconstriction.^388,389 Single-photon emission CT (SPECT) can also show regions of poor perfusion and delayed ischemia.³⁹⁰

Many treatments have been tried to prevent or treat vasoconstriction after SAH,³⁸⁶ including removal of blood by lumbar puncture and at the time of early surgery, pharmacologic agents such as calcium channel blockers to minimize vasospasm, and hypervolemia to prevent ischemia by maintaining perfusion. At present, the most popular approaches are early surgery, nimodipine (a calcium channel blocker), and hypervolemic therapy, especially after aneurysmal clipping. Hypovolemia is common after SAH, as is hyponatremia. Hypervolemia does not reverse the vasoconstriction but helps maintain brain perfusion.

Coagulopathies

Hypercoagulability and bleeding caused by decreased coagulability affect most body organs, including the brain and heart. An increased tendency for clotting can be caused by abnormalities of the formed blood elements or serologic factors.^{45,391,392,393} Increased numbers of red blood cells and platelets and qualitative abnormalities such as sickle cell disease can cause intravascular clotting, especially in the presence of dehydration. Excessive platelet activation, or so-called sticky platelets, can also explain increased coagulability.^394,395 The level of β-thromboglobulin is a good marker for platelet activation. Serologic abnormalities may be congenital or acquired. Decreased amounts of natural anticoagulants (antithrombin III, protein C, and protein S), resistance to activated protein C, and prothrombin gene mutations can cause hypercoagulability.^{391,392,393,396} These proteins may be decreased in patients with hypoproteinemia, especially that caused by the nephrotic syndrome and urinary protein loss. Fibrinogen levels and the levels of the various coagulation factors, such as factors VIII and XI, may also be high in patients with a prothrombotic state. In many of these patients—those on high-dose estrogen birth control pills, pregnant women, and patients with cancer—serologic and standard coagulation tests (in vitro) do not clarify the mechanism of the excessive clotting in vivo. Stroke patients may have serologic evidence of platelet activation and increased fibrin formation, but decreased natural fibrinolytic and anticoagulant activity.^392,396

Measurement of various serum antiphospholipid antibodies (APLAs) elicited considerable interest. The usually measured substances are the so-called lupus anticoagulant,^397,398,399 anticardiolipin antibodies, and β₂-glycoprotein 1 antibodies. Increased activity of APLAs is found in patients with systemic lupus erythematosus, acquired immunodeficiency syndrome (AIDS), giant cell arteritis, and Sneddon syndrome^{399,400,401,402} (livedo reticularis and strokes), as well as in association with the use of some drugs (eg, phenytoin, phenothiazines, procainamide, hydralazine, quinidine). When the APLAs are not associated with other conditions and the patient has clinical evidence of excess clotting, the disorder is considered to be primary and is referred to as the primary APLA syndrome.^{390,391,392,393} Patients with APLAs can have an increased incidence of spontaneous abortions, venous occlusive disease of the legs and pulmonary embolism, brain infarcts (often multiple), thrombocytopenia, and false-positive syphilis serologic tests. Older patients with APLAs often also have important risk factors for stroke.^{403,404,405,406}

Patients with systemic illnesses often have elevated erythrocyte sedimentation rates, and strokes and pulmonary emboli often follow and complicate MI. Customarily, such brain infarcts have been attributed to cardiogenic embolism, but some undoubtedly are related to thromboses precipitated by increased levels of acute-phase reactant coagulation proteins. Cancer, especially mucinous adenocarcinoma, has been associated with multiple vascular occlusions, large and tiny brain infarcts, and venous and arterial occlusions.⁴⁰⁷

Deficient coagulability can lead to serious intracranial bleeding. The hemorrhage can be into the brain (ICH), CSF (SAH), or subdural and epidural compartments. Thrombocytopenia, hemophilia, and leukemia are common conditions leading to intracranial hemorrhage. The most common iatrogenic cause of bleeding is anticoagulation with heparin or warfarin.⁴⁰⁸ Brain hemorrhage has also been described after fibrinolytic treatment of patients with coronary artery disease^409,410 and after rt-PA infusion to treat cerebrovascular occlusive disease.^{353,354,355,356,357,358,359,360}

Anticoagulant-related ICH, a catastrophic complication with high morbidity and mortality, is relatively rare considering the frequency of anticoagulant use. Anticoagulant-related hemorrhages develop more insidiously and evolve more slowly and more often than do other causes of ICH.^360,404 Many are erroneously attributed to brain ischemia. Any patient taking anticoagulants who develops CNS symptoms should be considered to have anticoagulant-related ICH until CT or MRI excludes the diagnosis. Many patients require surgical drainage of their hematomas to ensure survival. Anticoagulants should be stopped immediately and their effect reversed by fresh frozen plasma or vitamin K. It is probably safe to resume anticoagulation with heparin 7 days to 2 weeks after the ICH if indicated, such as for prophylaxis in patients with mechanical heart valves.⁴¹¹ In patients treated with fibrinolytic agents, hemorrhages are most often lobar or cerebellar and may be multiple. ICH is more common when there is a past stroke, when heparin or other agents that affect coagulation are given with or after fibrinolytic agents, and when there is a hemostatic defect secondary to treatment.^410,411

Arterial Dissection

Aortic dissections involving the innominate artery or CCA are a well-known cause of stroke and TIA. Less well known are the syndromes produced by dissections of the extracranial and intracranial cervicocephalic arteries, which are especially likely to occur in young, active individuals without risk factors for atherosclerosis or stroke, but after trauma or chiropractic or other neck manipulations. They are also associated with fibromuscular dysplasia, α₁-antitrypsin deficiency, Marfan syndrome, pseudoxanthoma elasticum, and migraine.

Dissections start with a tear in the media and spread longitudinally (Fig. 94–10), often disrupting adventitial fibers or even rupturing through the adventitia to produce an extravascular hematoma and a false aneurysm, or pseudoaneurysm, within muscle and connective tissue. Intracranially, such a rupture can produce SAH. Other dissections cause arterial obstruction and secondary thrombosis of the narrowed vascular lumen. Most cerebrovascular dissections occur in the extracranial vessels, particularly the pharyngeal portion of the ICA and the nuchal VAs.^{45,412,413,414,415,416,417}

Extracranial dissections produce sharp pain and throbbing headache; brain and retinal ischemic episodes, which may occur in rapid-fire attacks (carotid allegro⁴¹⁷); and pressure on adjacent structures, especially cranial nerves X through XII, which exit at the skull base. Strokes, usually from embolization of clots, are common but may have a benign course. Intracranial dissections have a poorer prognosis, often with vascular rupture and SAH. The diagnosis is confirmed by angiography, CT, or MRI. Ultrasound studies can be helpful in suggesting the diagnosis of dissection in the neck.⁴¹⁸

There is debate regarding the appropriate treatment for cervicocephalic arterial dissection. The Cervical Artery Dissection in Stroke Study (CADISS-NR) was a small trial enrolling 250 participants with cervicocephalic dissection (118 carotid, 132 vertebral), who were randomly assigned to receive antiplatelet or anticoagulants. The CADISS trial concluded that there was no difference in secondary stroke prevention provided by antiplatelet and anticoagulant agents in patients with carotid or vertebral artery dissections.⁴¹⁹ It is important to note that the mean time of treatment after symptom onset was 10.8 days (standard deviation 7.0, range 1-31 days) in this study. Extensive published data^420,421,422 as well as our personal experience show that most strokes develop within the first 7 days after brain ischemia and the rate of stroke thereafter is very low. In addition, strokes are uncommon in patients whose presentation does not include brain ischemia (neck pain, Horner syndrome, compression of nerve roots, or lower cranial nerves). These patients were also included in the trial. In CADISS-NR, only two patients had strokes within 3 months. In the meta-analysis included in the report, almost all of the patients were enrolled beyond 5 days after onset. Physicians must not take the results of this trial and the meta-analysis to conclude anything about treatment during the very acute period after brain symptom onset. This time period was not a part of the trial or the meta-analysis. In patients with brain ischemia, we generally would recommend that treatment consist of the use of heparin acutely, followed by warfarin. In patients in whom the dissected artery is initially occluded and remains occluded, warfarin can be stopped after 6 to 12 weeks, and an antiplatelet agent should then be initiated. The authors continue warfarin in other patients until severe luminal narrowing is no longer present, monitoring the dissected arteries with serial noninvasive techniques (ultrasound, CTA, or MRA) every few months. Intracranial dissections with SAH have been treated surgically.^413,423,424