Arman T. Askari, MD

A 61-year-old white man presents with progressive fatigue, which began several months ago and has accelerated in severity over the past week. He says he has had no shortness of breath, chest pain, or symptoms of heart failure, but he has noticed a decrease in exertional capacity and now has trouble completing his daily 5-mile walk.

He saw his primary physician, who obtained an electrocardiogram that showed a new left bundle branch block. Transthoracic echocardiography indicated that his left ventricular ejection fraction, which was 60% a year earlier, was now 35%.

He has hypertension, dyslipidemia, type 2 diabetes, and chronic kidney disease. Although he was previously morbidly obese, he has lost more than 100 pounds with diet and exercise over the past 10 years. He also used to smoke; in fact, he has a 30-pack-year history, but he quit in 1987. He has a family history of premature coronary artery disease.

Physical examination. His heart rate is 75 beats per minute, blood pressure 142/85 mm Hg, and blood oxygen saturation 96% while breathing room air. He weighs 169 pounds (76.6 kg) and he is 6 feet tall (182.9 cm), so his body mass index is 22.9 kg/m².

He is awake and in no acute distress. His breath sounds are normal, without crackles or wheezes. His heart has a normal rate and regular rhythm; he has normal first and second heart sounds and no extra sounds or murmurs; the apical impulse is not displaced. His abdomen is soft and nontender, with no hepatosplenomegaly or hepatojugular reflex. His extremities are warm and well perfused, with normal peripheral pulses and no edema. He has no gross neurologic defects.

Initial laboratory analysis (Table 1) shows evidence of anemia and renal insufficiency and a slightly elevated serum level of glucose. His cardiac biomarkers are within normal limits, but his B-type natriuretic peptide level is 483 pg/mL (reference range < 100 pg/mL). His thyroid-stimulating hormone level is in the normal range.

Electrocardiography reveals sinus rhythm with a left bundle branch block and left axis deviation (Figure 1), which were not present 1 year ago.

Chest roentgenography is normal.

A WORRISOME PICTURE

1. Which of the following is associated with left bundle branch block?

• Myocardial injury
• Hypertension
• Aortic stenosis
• Intrinsic conduction system disease
• All of the above

All of the above are true. For left bundle branch block to be diagnosed, the rhythm must be supraventricular and the QRS duration must be 120 ms or more. There should be a QS or RS complex in V₁ and a monophasic R wave in I and V₆. Also, the T wave should be deflected opposite the terminal deflection of the QRS complex. This is known as appropriate T-wave discordance with bundle branch block. A concordant T wave is nonspecific but suggests ischemia or myocardial infarction.

Potential causes of a new left bundle branch block include hypertension, acute myocardial infarction, aortic stenosis, and conduction system disease. A new left bundle branch block with a concomitant decrease in ejection fraction, especially in a patient with cardiac risk factors, is very worrisome, raising the possibility of ischemic heart disease.

MORE CARDIAC TESTING

The patient undergoes more cardiac testing.

Transthoracic echocardiography is done again. The left ventricle is normal in size, but the ejection fraction is 35%. In addition, stage 1 diastolic dysfunction (abnormal relaxation) and evidence of mechanical dyssynchrony (disruption in the normal sequence of activation and contraction of segments of the left ventricular wall) are seen. The right ventricle is normal in size and function. There is trivial mitral regurgitation and mild tricuspid regurgitation with normal right-sided pressures.

A gated rubidium-82 dipyridamole stress test yields no evidence of a fixed or reversible perfusion defect.

Left heart catheterization reveals angiographically normal coronary arteries.

Magnetic resonance imaging (MRI) shows a moderately hypertrophied left ventricle with moderately to severely depressed systolic function (left ventricular ejection fraction 27%). The left ventricle appears dyssynchronous. Delayed-enhancement imaging reveals patchy delayed enhancement in the basal septum and the basal inferolateral walls. These findings suggest cardiac sarcoidosis, with a sensitivity of nearly 100% and a specificity of approximately 78%.¹

SARCOIDOSIS IS A MULTISYSTEM DISEASE

Sarcoidosis is a multisystem disease characterized by noncaseating granulomas. Almost any organ can be affected, but it most commonly involves the respiratory and lymphatic systems.² Although infectious, environmental, and genetic factors have been implicated, the cause remains unknown. The prevalence is approximately 20 per 100,000, being higher in black³ and Japanese ⁴ populations.

 

CARDIAC SARCOIDOSIS

2. What percentage of patients with sarcoidosis have cardiac involvement?

• 10%–20%
• 20%–30%
• 50%
• 80%

Cardiac involvement is seen in 20% to 30% of patients with sarcoidosis.^5–7 However, most cases are subclinical, and symptomatic cardiac involvement is present in only about 5% of patients with systemic sarcoidosis.⁸ Isolated cardiac sarcoidosis has been described in case reports but is rare.⁹

The clinical manifestations of cardiac sarcoidosis depend on the location and extent of granulomatous inflammation. In a necropsy study of 113 patients with cardiac sarcoidosis, the left ventricular free wall was the most common location, followed by the interventricular septum.¹⁰

3. How does cardiac sarcoidosis most commonly present?

• Conduction abnormalities
• Ventricular tachycardia
• Cardiomyopathy
• Sudden death
• None of the above

Common presentations of cardiac sarcoidosis include conduction system disease and arrhythmias (which can sometimes result in sudden death), and heart failure.

Conduction abnormalities due to granulomas (in the active phase of sarcoidosis) and fibrosis (in the fibrotic phase) in the atrioventricular node or bundle of His are the most common presentation of cardiac sarcoidosis.⁹ These lesions may result in relatively benign first-degree heart block or may be as potentially devastating as complete heart block.

In almost all patients with conduction abnormalities, the basal interventricular septum is involved.¹¹ Patients who develop complete heart block from sarcoidosis tend to be younger than those with idiopathic heart block. Therefore, complete heart block in a young patient should raise the possibility of this diagnosis. ¹²

Ventricular tachycardia (sustained or nonsustained) and ventricular premature beats are the second most common presentation. Up to 22% of patients with sarcoidosis have electrocardiographic evidence of ventricular arrythmias. ¹³ The cause is believed to be myocardial scar tissue resulting from the sarcoid granulomas, leading to electrical reentry.¹⁴ Sudden death due to ventricular tachyarrhythmias or conduction blocks accounts for 25% to 65% of deaths from cardiac sarcoidosis.^9,15,16

Heart failure may result from sarcoidosis when there is extensive granulomatous disease in the myocardium. Depending on the location of the granulomas, both systolic and diastolic dysfunction can occur. In severe cases, extensive granulomas can cause left ventricular aneurysms.

The diagnosis of cardiac sarcoidosis as the cause of heart failure can be difficult to establish, especially in patients without evidence of sarcoidosis elsewhere. Such patients are often given a diagnosis of idiopathic dilated cardiomyopathy. However, compared with patients with idiopathic dilated cardiomyopathy, those with cardiac sarcoidosis have a greater incidence of advanced atrioventricular block, abnormal wall thickness, focal wall motion abnormalities, and perfusion defects of the anteroseptal and apical regions.¹⁷

Progressive heart failure is the second most frequent cause of death (after sudden death) and accounts for 25% to 75% of sarcoid-related cardiac deaths.^9,18,19

DIAGNOSING CARDIAC SARCOIDOSIS

4. How is cardiac sarcoidosis diagnosed?

• Electrocardiography
• Echocardiography
• Computed tomography
• Endomyocardial biopsy
• There are no guidelines for diagnosis

Given the variable extent and location of granulomas in sarcoidosis, the diagnosis of cardiac sarcoidosis is often challenging.

To make the diagnosis of sarcoidosis in general, the American Thoracic Society² says that the clinical picture should be compatible with this diagnosis, noncaseating granulomas should be histologically confirmed, and other diseases capable of producing a similar clinical or histologic picture should be excluded.

A newer diagnostic tool, the Sarcoidosis Three-Dimensional Assessment Instrument,²⁰ incorporates two earlier tools.^20,21 It assesses three axes: organ involvement, sarcoidosis severity, and sarcoidosis activity and categorizes the diagnosis of sarcoidosis as “definite,” “probable,” or “possible.”²⁰

In Japan, where sarcoidosis is more common, the Ministry of Health and Welfare²² says that cardiac sarcoidosis can be diagnosed histologically if operative or endomyocardial biopsy specimens contain noncaseating granuloma. In addition, the diagnosis can be suspected in patients who have a histologic diagnosis of extracardiac sarcoidosis if the first item in the list below and one or more of the rest are present:

• Complete right bundle branch block, left axis deviation, atrioventricular block, ventricular tachycardia, premature ventricular contractions (> grade 2 of the Lown classification), or Q or ST-T wave abnormalities
• Abnormal wall motion, regional wall thinning, or dilation of the left ventricle on echocardiography
• Perfusion defects on thallium 201 myocardial scintigraphy or abnormal accumulation of gallium citrate Ga 67 or technetium 99m on myocardial scintigraphy
• Abnormal intracardiac pressure, low cardiac output, or abnormal wall motion or depressed left ventricular ejection fraction on cardiac catheterization
• Nonspecific interstitial fibrosis or cellular infiltration on myocardial biopsy.

The current diagnostic guidelines from the American Thoracic Society² and the Japanese Ministry of Health and Welfare²² and the Sarcoidosis Three-Dimensional Assessment Instrument,²⁰ however, do not incorporate newer imaging studies as part of their criteria.

 

A DEFINITIVE DIAGNOSIS

5. Endomyocardial biopsy often provides the definitive diagnosis of cardiac sarcoidosis.

• True
• False

False. Endomyocardial biopsy often fails to reveal noncaseating granulomas, which have a patchy distribution.¹³ Table 2 summarizes the accuracy of tests for cardiac sarcoidosis.

Electrocardiography is abnormal in up to 50% of patients with sarcoidosis,²³ reflecting the conduction disease or arrhythmias commonly seen in cardiac involvement.

Chest radiography classically shows hilar lymphadenopathy and interstitial disease, and may show cardiomegaly, pericardial effusion, or left ventricular aneurysm.

Echocardiography is nonspecific for sarcoid disease, but granulomatous involvement and scar tissue of cardiac tissue may appear hyperechogenic, particularly in the ventricular septum or left ventricular free wall.²⁴

Angiography. Primary sarcoidosis rarely involves the coronary arteries,²⁵ so angiography is most useful in excluding the diagnosis of atherosclerotic coronary artery disease.

Radionuclide imaging with thallium 201 in patients with suspected cardiac sarcoidosis may be useful to suggest myocardial involvement and to exclude cardiac dysfunction secondary to coronary artery disease. Segmental areas with defective thallium 201 uptake correspond to fibrogranulomatous tissue. In resting images, the pattern may be similar to that seen in coronary artery disease. However, during exercise, perfusion defects increase in patients who have ischemia but actually decrease in those with cardiac sarcoidosis.²⁶

Nevertheless, some conclude that thallium scanning is too nonspecific for it to be used as a diagnostic or screening test.^27,28 The combined use of thallium 201 and gallium 67 may better detect cardiac sarcoidosis, as gallium is taken up in areas of active inflammation.

Positron-emission tomography (PET) with fluorodeoxyglucose F 18 (FDG), with the patient fasting, appears to be useful in detecting the early inflammation of cardiac sarcoidosis^29–34 and monitoring disease activity.^30,31 FDG is a glucose analogue that is taken up by granulomatous tissue in the myocardium.³⁴ The uptake in cardiac sarcoidosis is in a focal distribution.^30,31,34 The abnormal FDG uptake resolves with steroid treatment.^31,32

MRI has promise for diagnosing cardiac sarcoidosis. With gadolinium contrast, MRI has superior image resolution and can detect cardiac involvement early in its course.^{27,29,35–44}

Inflammation of the myocardium due to sarcoid involvement appears as focal zones of increased signal intensity on both T2-weighted and early gadolinium T1-weighted images. Late myocardial enhancement after gadolinium infusion is the most typical finding of cardiac sarcoidosis on MRI, and likely represents fibrogranulomatous tissue.²⁷ Delayed gadolinium enhancement is also seen in myocardial infarction but differs in its distribution.^1,35,45 Cardiac sarcoidosis most commonly affects the basal and lateral segments. In one study, the finding of delayed enhancement had a sensitivity of 100% and a specificity of 78%,^1,27 though it may not sufficiently differentiate active inflammation from scar.³⁰

Like FDG-PET, MRI has also been shown to be useful for monitoring treatment.^33,46 However, PET is more useful for follow-up in patients who receive a pacemaker or implantable cardioverter-defibrillator, in whom MRI is contraindicated. One case report²⁹ described using both delayed-enhancement MRI and FDG-PET to diagnose cardiac sarcoidosis.

TREATMENT

6. How is cardiac sarcoidosis currently treated?

• Implantable cardioverter-defibrillator
• Corticosteroids
• Heart transplantation
• All of the above
• None of the above

Corticosteroids

Corticosteroids are the mainstay of treatment of cardiac sarcoidosis, as they attenuate the characteristic inflammation and fibrosis of sarcoid granulomas. The goal is to prevent compromise of cardiac structure or function.⁴⁷ Although most of the supporting data are anecdotal, steroids have been shown to improve ventricular contractility,⁴⁸ arrhythmias,⁴⁹ and conduction abnormalities.⁵⁰ MRI and FDG-PET studies have shown cardiac lesions resolving after steroids were started.^31,45,46

The optimal dosage remains unknown. Initial doses of 30 to 60 mg daily, gradually tapered over 6 to 12 months to maintenance doses of 5 to 10 mg daily, have been effective.^45,51

Relapses are common and require vigilant monitoring.

Alternative agents such as cyclophosphamide (Cytoxan),⁵² methotrexate (Rheumatrex), ⁵³ and cyclosporine (Sandimmune)⁵⁴ can be given to patients whose disease does not respond to corticosteroids or who cannot tolerate their side effects.

Implantable cardioverter-defibrillator

Sudden death due to ventricular tachyarrhythmias or conduction block accounts for 30% to 65% of deaths in patients with cardiac sarcoidosis.¹⁰ The rates of recurrent ventricular tachycardia and sudden death are high, even with antiarrhythmic drug therapy.⁵⁵

Although experience with implantable cardiac defibrillators is limited in patients with cardiac sarcoidosis,^55–58 some have argued that they be strongly considered to prevent sudden cardiac death in this high-risk group.^57,58

Heart transplantation

The largest body of data on transplantation comes from the United Network for Organ Sharing database. In the 65 patients with cardiac sarcoidosis who underwent cardiac transplantation in the 18 years from October 1987 to September 2005, the 1-year post-transplant survival rate was 88%, which was better than in patients with all other diagnoses (85%). The 5-year survival rate was 80%.^59,60

Recurrence of sarcoidosis within the cardiac allograft and transmission of sarcoidosis from donor to recipient have both been documented after heart transplantation.^61,62

 

CAUSES OF DEATH

7. What is the most common cause of death in patients with cardiac sarcoidosis?

• Respiratory failure
• Conduction disturbances
• Progressive heart failure
• Ventricular tachyarrhythmias
• None of the above

The prognosis of symptomatic cardiac sarcoidosis is not well defined, owing to the variable extent and severity of the disease. The mortality rate in sarcoidosis without cardiac involvement is about 1% to 5% per year.^63,64 Cardiac involvement portends a worse prognosis, with a 55% survival rate at 5 years and 44% at 10 years.^17,65 Most patients in the reported series ultimately died of cardiac complications of sarcoidosis, including ventricular tachyarrhythmias, conduction disturbances, and progressive cardiomyopathy.^10,17

Since corticosteroids, pacemakers, and implantable cardioverter-defibrillators have begun to be used, the cause of death has shifted from sudden death to progressive heart failure.⁶⁶

CASE CONTINUED

While hospitalized, our patient had two episodes of nonsustained ventricular tachycardia (7 and 12 beats) on telemetry. Cardiac MRI showed a lesion in the basal septum most likely involving the left bundle and an area of lateral basilar involvement near the mitral annulus (Figure 2). Ventricular dyssynchrony was clearly evident on both echocardiography and MRI, with depressed left ventricular function (ejection fraction 28% on MRI, 35% on echocardiography).

Electrophysiologic testing revealed inducible monomorphic sustained ventricular tachycardia. The patient subsequently had a biventricular cardioverter-defibrillator implanted. He was started on an angiotensin-converting enzyme inhibitor and a beta-blocker for his heart failure. Further imaging of his chest and abdomen revealed lesions in his thyroid and liver. As of this writing, he is undergoing further workup. Because of active infection with Clostridium difficile, steroid therapy was deferred.

A 61-year-old white man presents with progressive fatigue, which began several months ago and has accelerated in severity over the past week. He says he has had no shortness of breath, chest pain, or symptoms of heart failure, but he has noticed a decrease in exertional capacity and now has trouble completing his daily 5-mile walk.

He saw his primary physician, who obtained an electrocardiogram that showed a new left bundle branch block. Transthoracic echocardiography indicated that his left ventricular ejection fraction, which was 60% a year earlier, was now 35%.

He has hypertension, dyslipidemia, type 2 diabetes, and chronic kidney disease. Although he was previously morbidly obese, he has lost more than 100 pounds with diet and exercise over the past 10 years. He also used to smoke; in fact, he has a 30-pack-year history, but he quit in 1987. He has a family history of premature coronary artery disease.

Physical examination. His heart rate is 75 beats per minute, blood pressure 142/85 mm Hg, and blood oxygen saturation 96% while breathing room air. He weighs 169 pounds (76.6 kg) and he is 6 feet tall (182.9 cm), so his body mass index is 22.9 kg/m².

He is awake and in no acute distress. His breath sounds are normal, without crackles or wheezes. His heart has a normal rate and regular rhythm; he has normal first and second heart sounds and no extra sounds or murmurs; the apical impulse is not displaced. His abdomen is soft and nontender, with no hepatosplenomegaly or hepatojugular reflex. His extremities are warm and well perfused, with normal peripheral pulses and no edema. He has no gross neurologic defects.

Initial laboratory analysis (Table 1) shows evidence of anemia and renal insufficiency and a slightly elevated serum level of glucose. His cardiac biomarkers are within normal limits, but his B-type natriuretic peptide level is 483 pg/mL (reference range < 100 pg/mL). His thyroid-stimulating hormone level is in the normal range.

Electrocardiography reveals sinus rhythm with a left bundle branch block and left axis deviation (Figure 1), which were not present 1 year ago.

Chest roentgenography is normal.

A WORRISOME PICTURE

1. Which of the following is associated with left bundle branch block?

• Myocardial injury
• Hypertension
• Aortic stenosis
• Intrinsic conduction system disease
• All of the above

All of the above are true. For left bundle branch block to be diagnosed, the rhythm must be supraventricular and the QRS duration must be 120 ms or more. There should be a QS or RS complex in V₁ and a monophasic R wave in I and V₆. Also, the T wave should be deflected opposite the terminal deflection of the QRS complex. This is known as appropriate T-wave discordance with bundle branch block. A concordant T wave is nonspecific but suggests ischemia or myocardial infarction.

Potential causes of a new left bundle branch block include hypertension, acute myocardial infarction, aortic stenosis, and conduction system disease. A new left bundle branch block with a concomitant decrease in ejection fraction, especially in a patient with cardiac risk factors, is very worrisome, raising the possibility of ischemic heart disease.

MORE CARDIAC TESTING

The patient undergoes more cardiac testing.

Transthoracic echocardiography is done again. The left ventricle is normal in size, but the ejection fraction is 35%. In addition, stage 1 diastolic dysfunction (abnormal relaxation) and evidence of mechanical dyssynchrony (disruption in the normal sequence of activation and contraction of segments of the left ventricular wall) are seen. The right ventricle is normal in size and function. There is trivial mitral regurgitation and mild tricuspid regurgitation with normal right-sided pressures.

A gated rubidium-82 dipyridamole stress test yields no evidence of a fixed or reversible perfusion defect.

Left heart catheterization reveals angiographically normal coronary arteries.

Magnetic resonance imaging (MRI) shows a moderately hypertrophied left ventricle with moderately to severely depressed systolic function (left ventricular ejection fraction 27%). The left ventricle appears dyssynchronous. Delayed-enhancement imaging reveals patchy delayed enhancement in the basal septum and the basal inferolateral walls. These findings suggest cardiac sarcoidosis, with a sensitivity of nearly 100% and a specificity of approximately 78%.¹

SARCOIDOSIS IS A MULTISYSTEM DISEASE

Sarcoidosis is a multisystem disease characterized by noncaseating granulomas. Almost any organ can be affected, but it most commonly involves the respiratory and lymphatic systems.² Although infectious, environmental, and genetic factors have been implicated, the cause remains unknown. The prevalence is approximately 20 per 100,000, being higher in black³ and Japanese ⁴ populations.

 

CARDIAC SARCOIDOSIS

2. What percentage of patients with sarcoidosis have cardiac involvement?

• 10%–20%
• 20%–30%
• 50%
• 80%

Cardiac involvement is seen in 20% to 30% of patients with sarcoidosis.^5–7 However, most cases are subclinical, and symptomatic cardiac involvement is present in only about 5% of patients with systemic sarcoidosis.⁸ Isolated cardiac sarcoidosis has been described in case reports but is rare.⁹

The clinical manifestations of cardiac sarcoidosis depend on the location and extent of granulomatous inflammation. In a necropsy study of 113 patients with cardiac sarcoidosis, the left ventricular free wall was the most common location, followed by the interventricular septum.¹⁰

3. How does cardiac sarcoidosis most commonly present?

• Conduction abnormalities
• Ventricular tachycardia
• Cardiomyopathy
• Sudden death
• None of the above

Common presentations of cardiac sarcoidosis include conduction system disease and arrhythmias (which can sometimes result in sudden death), and heart failure.

Conduction abnormalities due to granulomas (in the active phase of sarcoidosis) and fibrosis (in the fibrotic phase) in the atrioventricular node or bundle of His are the most common presentation of cardiac sarcoidosis.⁹ These lesions may result in relatively benign first-degree heart block or may be as potentially devastating as complete heart block.

In almost all patients with conduction abnormalities, the basal interventricular septum is involved.¹¹ Patients who develop complete heart block from sarcoidosis tend to be younger than those with idiopathic heart block. Therefore, complete heart block in a young patient should raise the possibility of this diagnosis. ¹²

Ventricular tachycardia (sustained or nonsustained) and ventricular premature beats are the second most common presentation. Up to 22% of patients with sarcoidosis have electrocardiographic evidence of ventricular arrythmias. ¹³ The cause is believed to be myocardial scar tissue resulting from the sarcoid granulomas, leading to electrical reentry.¹⁴ Sudden death due to ventricular tachyarrhythmias or conduction blocks accounts for 25% to 65% of deaths from cardiac sarcoidosis.^9,15,16

Heart failure may result from sarcoidosis when there is extensive granulomatous disease in the myocardium. Depending on the location of the granulomas, both systolic and diastolic dysfunction can occur. In severe cases, extensive granulomas can cause left ventricular aneurysms.

The diagnosis of cardiac sarcoidosis as the cause of heart failure can be difficult to establish, especially in patients without evidence of sarcoidosis elsewhere. Such patients are often given a diagnosis of idiopathic dilated cardiomyopathy. However, compared with patients with idiopathic dilated cardiomyopathy, those with cardiac sarcoidosis have a greater incidence of advanced atrioventricular block, abnormal wall thickness, focal wall motion abnormalities, and perfusion defects of the anteroseptal and apical regions.¹⁷

Progressive heart failure is the second most frequent cause of death (after sudden death) and accounts for 25% to 75% of sarcoid-related cardiac deaths.^9,18,19

DIAGNOSING CARDIAC SARCOIDOSIS

4. How is cardiac sarcoidosis diagnosed?

• Electrocardiography
• Echocardiography
• Computed tomography
• Endomyocardial biopsy
• There are no guidelines for diagnosis

Given the variable extent and location of granulomas in sarcoidosis, the diagnosis of cardiac sarcoidosis is often challenging.

To make the diagnosis of sarcoidosis in general, the American Thoracic Society² says that the clinical picture should be compatible with this diagnosis, noncaseating granulomas should be histologically confirmed, and other diseases capable of producing a similar clinical or histologic picture should be excluded.

A newer diagnostic tool, the Sarcoidosis Three-Dimensional Assessment Instrument,²⁰ incorporates two earlier tools.^20,21 It assesses three axes: organ involvement, sarcoidosis severity, and sarcoidosis activity and categorizes the diagnosis of sarcoidosis as “definite,” “probable,” or “possible.”²⁰

In Japan, where sarcoidosis is more common, the Ministry of Health and Welfare²² says that cardiac sarcoidosis can be diagnosed histologically if operative or endomyocardial biopsy specimens contain noncaseating granuloma. In addition, the diagnosis can be suspected in patients who have a histologic diagnosis of extracardiac sarcoidosis if the first item in the list below and one or more of the rest are present:

• Complete right bundle branch block, left axis deviation, atrioventricular block, ventricular tachycardia, premature ventricular contractions (> grade 2 of the Lown classification), or Q or ST-T wave abnormalities
• Abnormal wall motion, regional wall thinning, or dilation of the left ventricle on echocardiography
• Perfusion defects on thallium 201 myocardial scintigraphy or abnormal accumulation of gallium citrate Ga 67 or technetium 99m on myocardial scintigraphy
• Abnormal intracardiac pressure, low cardiac output, or abnormal wall motion or depressed left ventricular ejection fraction on cardiac catheterization
• Nonspecific interstitial fibrosis or cellular infiltration on myocardial biopsy.

The current diagnostic guidelines from the American Thoracic Society² and the Japanese Ministry of Health and Welfare²² and the Sarcoidosis Three-Dimensional Assessment Instrument,²⁰ however, do not incorporate newer imaging studies as part of their criteria.

 

A DEFINITIVE DIAGNOSIS

5. Endomyocardial biopsy often provides the definitive diagnosis of cardiac sarcoidosis.

• True
• False

False. Endomyocardial biopsy often fails to reveal noncaseating granulomas, which have a patchy distribution.¹³ Table 2 summarizes the accuracy of tests for cardiac sarcoidosis.

Electrocardiography is abnormal in up to 50% of patients with sarcoidosis,²³ reflecting the conduction disease or arrhythmias commonly seen in cardiac involvement.

Chest radiography classically shows hilar lymphadenopathy and interstitial disease, and may show cardiomegaly, pericardial effusion, or left ventricular aneurysm.

Echocardiography is nonspecific for sarcoid disease, but granulomatous involvement and scar tissue of cardiac tissue may appear hyperechogenic, particularly in the ventricular septum or left ventricular free wall.²⁴

Angiography. Primary sarcoidosis rarely involves the coronary arteries,²⁵ so angiography is most useful in excluding the diagnosis of atherosclerotic coronary artery disease.

Radionuclide imaging with thallium 201 in patients with suspected cardiac sarcoidosis may be useful to suggest myocardial involvement and to exclude cardiac dysfunction secondary to coronary artery disease. Segmental areas with defective thallium 201 uptake correspond to fibrogranulomatous tissue. In resting images, the pattern may be similar to that seen in coronary artery disease. However, during exercise, perfusion defects increase in patients who have ischemia but actually decrease in those with cardiac sarcoidosis.²⁶

Nevertheless, some conclude that thallium scanning is too nonspecific for it to be used as a diagnostic or screening test.^27,28 The combined use of thallium 201 and gallium 67 may better detect cardiac sarcoidosis, as gallium is taken up in areas of active inflammation.

Positron-emission tomography (PET) with fluorodeoxyglucose F 18 (FDG), with the patient fasting, appears to be useful in detecting the early inflammation of cardiac sarcoidosis^29–34 and monitoring disease activity.^30,31 FDG is a glucose analogue that is taken up by granulomatous tissue in the myocardium.³⁴ The uptake in cardiac sarcoidosis is in a focal distribution.^30,31,34 The abnormal FDG uptake resolves with steroid treatment.^31,32

MRI has promise for diagnosing cardiac sarcoidosis. With gadolinium contrast, MRI has superior image resolution and can detect cardiac involvement early in its course.^{27,29,35–44}

Inflammation of the myocardium due to sarcoid involvement appears as focal zones of increased signal intensity on both T2-weighted and early gadolinium T1-weighted images. Late myocardial enhancement after gadolinium infusion is the most typical finding of cardiac sarcoidosis on MRI, and likely represents fibrogranulomatous tissue.²⁷ Delayed gadolinium enhancement is also seen in myocardial infarction but differs in its distribution.^1,35,45 Cardiac sarcoidosis most commonly affects the basal and lateral segments. In one study, the finding of delayed enhancement had a sensitivity of 100% and a specificity of 78%,^1,27 though it may not sufficiently differentiate active inflammation from scar.³⁰

Like FDG-PET, MRI has also been shown to be useful for monitoring treatment.^33,46 However, PET is more useful for follow-up in patients who receive a pacemaker or implantable cardioverter-defibrillator, in whom MRI is contraindicated. One case report²⁹ described using both delayed-enhancement MRI and FDG-PET to diagnose cardiac sarcoidosis.

TREATMENT

6. How is cardiac sarcoidosis currently treated?

• Implantable cardioverter-defibrillator
• Corticosteroids
• Heart transplantation
• All of the above
• None of the above

Corticosteroids

Corticosteroids are the mainstay of treatment of cardiac sarcoidosis, as they attenuate the characteristic inflammation and fibrosis of sarcoid granulomas. The goal is to prevent compromise of cardiac structure or function.⁴⁷ Although most of the supporting data are anecdotal, steroids have been shown to improve ventricular contractility,⁴⁸ arrhythmias,⁴⁹ and conduction abnormalities.⁵⁰ MRI and FDG-PET studies have shown cardiac lesions resolving after steroids were started.^31,45,46

The optimal dosage remains unknown. Initial doses of 30 to 60 mg daily, gradually tapered over 6 to 12 months to maintenance doses of 5 to 10 mg daily, have been effective.^45,51

Relapses are common and require vigilant monitoring.

Alternative agents such as cyclophosphamide (Cytoxan),⁵² methotrexate (Rheumatrex), ⁵³ and cyclosporine (Sandimmune)⁵⁴ can be given to patients whose disease does not respond to corticosteroids or who cannot tolerate their side effects.

Implantable cardioverter-defibrillator

Sudden death due to ventricular tachyarrhythmias or conduction block accounts for 30% to 65% of deaths in patients with cardiac sarcoidosis.¹⁰ The rates of recurrent ventricular tachycardia and sudden death are high, even with antiarrhythmic drug therapy.⁵⁵

Although experience with implantable cardiac defibrillators is limited in patients with cardiac sarcoidosis,^55–58 some have argued that they be strongly considered to prevent sudden cardiac death in this high-risk group.^57,58

Heart transplantation

The largest body of data on transplantation comes from the United Network for Organ Sharing database. In the 65 patients with cardiac sarcoidosis who underwent cardiac transplantation in the 18 years from October 1987 to September 2005, the 1-year post-transplant survival rate was 88%, which was better than in patients with all other diagnoses (85%). The 5-year survival rate was 80%.^59,60

Recurrence of sarcoidosis within the cardiac allograft and transmission of sarcoidosis from donor to recipient have both been documented after heart transplantation.^61,62

 

CAUSES OF DEATH

7. What is the most common cause of death in patients with cardiac sarcoidosis?

• Respiratory failure
• Conduction disturbances
• Progressive heart failure
• Ventricular tachyarrhythmias
• None of the above

The prognosis of symptomatic cardiac sarcoidosis is not well defined, owing to the variable extent and severity of the disease. The mortality rate in sarcoidosis without cardiac involvement is about 1% to 5% per year.^63,64 Cardiac involvement portends a worse prognosis, with a 55% survival rate at 5 years and 44% at 10 years.^17,65 Most patients in the reported series ultimately died of cardiac complications of sarcoidosis, including ventricular tachyarrhythmias, conduction disturbances, and progressive cardiomyopathy.^10,17

Since corticosteroids, pacemakers, and implantable cardioverter-defibrillators have begun to be used, the cause of death has shifted from sudden death to progressive heart failure.⁶⁶

CASE CONTINUED

While hospitalized, our patient had two episodes of nonsustained ventricular tachycardia (7 and 12 beats) on telemetry. Cardiac MRI showed a lesion in the basal septum most likely involving the left bundle and an area of lateral basilar involvement near the mitral annulus (Figure 2). Ventricular dyssynchrony was clearly evident on both echocardiography and MRI, with depressed left ventricular function (ejection fraction 28% on MRI, 35% on echocardiography).

Electrophysiologic testing revealed inducible monomorphic sustained ventricular tachycardia. The patient subsequently had a biventricular cardioverter-defibrillator implanted. He was started on an angiotensin-converting enzyme inhibitor and a beta-blocker for his heart failure. Further imaging of his chest and abdomen revealed lesions in his thyroid and liver. As of this writing, he is undergoing further workup. Because of active infection with Clostridium difficile, steroid therapy was deferred.

A 61-year-old white man presents with progressive fatigue, which began several months ago and has accelerated in severity over the past week. He says he has had no shortness of breath, chest pain, or symptoms of heart failure, but he has noticed a decrease in exertional capacity and now has trouble completing his daily 5-mile walk.

He saw his primary physician, who obtained an electrocardiogram that showed a new left bundle branch block. Transthoracic echocardiography indicated that his left ventricular ejection fraction, which was 60% a year earlier, was now 35%.

He has hypertension, dyslipidemia, type 2 diabetes, and chronic kidney disease. Although he was previously morbidly obese, he has lost more than 100 pounds with diet and exercise over the past 10 years. He also used to smoke; in fact, he has a 30-pack-year history, but he quit in 1987. He has a family history of premature coronary artery disease.

Physical examination. His heart rate is 75 beats per minute, blood pressure 142/85 mm Hg, and blood oxygen saturation 96% while breathing room air. He weighs 169 pounds (76.6 kg) and he is 6 feet tall (182.9 cm), so his body mass index is 22.9 kg/m².

He is awake and in no acute distress. His breath sounds are normal, without crackles or wheezes. His heart has a normal rate and regular rhythm; he has normal first and second heart sounds and no extra sounds or murmurs; the apical impulse is not displaced. His abdomen is soft and nontender, with no hepatosplenomegaly or hepatojugular reflex. His extremities are warm and well perfused, with normal peripheral pulses and no edema. He has no gross neurologic defects.

Initial laboratory analysis (Table 1) shows evidence of anemia and renal insufficiency and a slightly elevated serum level of glucose. His cardiac biomarkers are within normal limits, but his B-type natriuretic peptide level is 483 pg/mL (reference range < 100 pg/mL). His thyroid-stimulating hormone level is in the normal range.

Electrocardiography reveals sinus rhythm with a left bundle branch block and left axis deviation (Figure 1), which were not present 1 year ago.

Chest roentgenography is normal.

A WORRISOME PICTURE

1. Which of the following is associated with left bundle branch block?

• Myocardial injury
• Hypertension
• Aortic stenosis
• Intrinsic conduction system disease
• All of the above

All of the above are true. For left bundle branch block to be diagnosed, the rhythm must be supraventricular and the QRS duration must be 120 ms or more. There should be a QS or RS complex in V₁ and a monophasic R wave in I and V₆. Also, the T wave should be deflected opposite the terminal deflection of the QRS complex. This is known as appropriate T-wave discordance with bundle branch block. A concordant T wave is nonspecific but suggests ischemia or myocardial infarction.

Potential causes of a new left bundle branch block include hypertension, acute myocardial infarction, aortic stenosis, and conduction system disease. A new left bundle branch block with a concomitant decrease in ejection fraction, especially in a patient with cardiac risk factors, is very worrisome, raising the possibility of ischemic heart disease.

MORE CARDIAC TESTING

The patient undergoes more cardiac testing.

Transthoracic echocardiography is done again. The left ventricle is normal in size, but the ejection fraction is 35%. In addition, stage 1 diastolic dysfunction (abnormal relaxation) and evidence of mechanical dyssynchrony (disruption in the normal sequence of activation and contraction of segments of the left ventricular wall) are seen. The right ventricle is normal in size and function. There is trivial mitral regurgitation and mild tricuspid regurgitation with normal right-sided pressures.

A gated rubidium-82 dipyridamole stress test yields no evidence of a fixed or reversible perfusion defect.

Left heart catheterization reveals angiographically normal coronary arteries.

Magnetic resonance imaging (MRI) shows a moderately hypertrophied left ventricle with moderately to severely depressed systolic function (left ventricular ejection fraction 27%). The left ventricle appears dyssynchronous. Delayed-enhancement imaging reveals patchy delayed enhancement in the basal septum and the basal inferolateral walls. These findings suggest cardiac sarcoidosis, with a sensitivity of nearly 100% and a specificity of approximately 78%.¹

SARCOIDOSIS IS A MULTISYSTEM DISEASE

Sarcoidosis is a multisystem disease characterized by noncaseating granulomas. Almost any organ can be affected, but it most commonly involves the respiratory and lymphatic systems.² Although infectious, environmental, and genetic factors have been implicated, the cause remains unknown. The prevalence is approximately 20 per 100,000, being higher in black³ and Japanese ⁴ populations.

 

CARDIAC SARCOIDOSIS

2. What percentage of patients with sarcoidosis have cardiac involvement?

• 10%–20%
• 20%–30%
• 50%
• 80%

Cardiac involvement is seen in 20% to 30% of patients with sarcoidosis.^5–7 However, most cases are subclinical, and symptomatic cardiac involvement is present in only about 5% of patients with systemic sarcoidosis.⁸ Isolated cardiac sarcoidosis has been described in case reports but is rare.⁹

The clinical manifestations of cardiac sarcoidosis depend on the location and extent of granulomatous inflammation. In a necropsy study of 113 patients with cardiac sarcoidosis, the left ventricular free wall was the most common location, followed by the interventricular septum.¹⁰

3. How does cardiac sarcoidosis most commonly present?

• Conduction abnormalities
• Ventricular tachycardia
• Cardiomyopathy
• Sudden death
• None of the above

Common presentations of cardiac sarcoidosis include conduction system disease and arrhythmias (which can sometimes result in sudden death), and heart failure.

Conduction abnormalities due to granulomas (in the active phase of sarcoidosis) and fibrosis (in the fibrotic phase) in the atrioventricular node or bundle of His are the most common presentation of cardiac sarcoidosis.⁹ These lesions may result in relatively benign first-degree heart block or may be as potentially devastating as complete heart block.

In almost all patients with conduction abnormalities, the basal interventricular septum is involved.¹¹ Patients who develop complete heart block from sarcoidosis tend to be younger than those with idiopathic heart block. Therefore, complete heart block in a young patient should raise the possibility of this diagnosis. ¹²

Ventricular tachycardia (sustained or nonsustained) and ventricular premature beats are the second most common presentation. Up to 22% of patients with sarcoidosis have electrocardiographic evidence of ventricular arrythmias. ¹³ The cause is believed to be myocardial scar tissue resulting from the sarcoid granulomas, leading to electrical reentry.¹⁴ Sudden death due to ventricular tachyarrhythmias or conduction blocks accounts for 25% to 65% of deaths from cardiac sarcoidosis.^9,15,16

Heart failure may result from sarcoidosis when there is extensive granulomatous disease in the myocardium. Depending on the location of the granulomas, both systolic and diastolic dysfunction can occur. In severe cases, extensive granulomas can cause left ventricular aneurysms.

The diagnosis of cardiac sarcoidosis as the cause of heart failure can be difficult to establish, especially in patients without evidence of sarcoidosis elsewhere. Such patients are often given a diagnosis of idiopathic dilated cardiomyopathy. However, compared with patients with idiopathic dilated cardiomyopathy, those with cardiac sarcoidosis have a greater incidence of advanced atrioventricular block, abnormal wall thickness, focal wall motion abnormalities, and perfusion defects of the anteroseptal and apical regions.¹⁷

Progressive heart failure is the second most frequent cause of death (after sudden death) and accounts for 25% to 75% of sarcoid-related cardiac deaths.^9,18,19

DIAGNOSING CARDIAC SARCOIDOSIS

4. How is cardiac sarcoidosis diagnosed?

• Electrocardiography
• Echocardiography
• Computed tomography
• Endomyocardial biopsy
• There are no guidelines for diagnosis

Given the variable extent and location of granulomas in sarcoidosis, the diagnosis of cardiac sarcoidosis is often challenging.

To make the diagnosis of sarcoidosis in general, the American Thoracic Society² says that the clinical picture should be compatible with this diagnosis, noncaseating granulomas should be histologically confirmed, and other diseases capable of producing a similar clinical or histologic picture should be excluded.

A newer diagnostic tool, the Sarcoidosis Three-Dimensional Assessment Instrument,²⁰ incorporates two earlier tools.^20,21 It assesses three axes: organ involvement, sarcoidosis severity, and sarcoidosis activity and categorizes the diagnosis of sarcoidosis as “definite,” “probable,” or “possible.”²⁰

In Japan, where sarcoidosis is more common, the Ministry of Health and Welfare²² says that cardiac sarcoidosis can be diagnosed histologically if operative or endomyocardial biopsy specimens contain noncaseating granuloma. In addition, the diagnosis can be suspected in patients who have a histologic diagnosis of extracardiac sarcoidosis if the first item in the list below and one or more of the rest are present:

• Complete right bundle branch block, left axis deviation, atrioventricular block, ventricular tachycardia, premature ventricular contractions (> grade 2 of the Lown classification), or Q or ST-T wave abnormalities
• Abnormal wall motion, regional wall thinning, or dilation of the left ventricle on echocardiography
• Perfusion defects on thallium 201 myocardial scintigraphy or abnormal accumulation of gallium citrate Ga 67 or technetium 99m on myocardial scintigraphy
• Abnormal intracardiac pressure, low cardiac output, or abnormal wall motion or depressed left ventricular ejection fraction on cardiac catheterization
• Nonspecific interstitial fibrosis or cellular infiltration on myocardial biopsy.

The current diagnostic guidelines from the American Thoracic Society² and the Japanese Ministry of Health and Welfare²² and the Sarcoidosis Three-Dimensional Assessment Instrument,²⁰ however, do not incorporate newer imaging studies as part of their criteria.

 

A DEFINITIVE DIAGNOSIS

5. Endomyocardial biopsy often provides the definitive diagnosis of cardiac sarcoidosis.

• True
• False

False. Endomyocardial biopsy often fails to reveal noncaseating granulomas, which have a patchy distribution.¹³ Table 2 summarizes the accuracy of tests for cardiac sarcoidosis.

Electrocardiography is abnormal in up to 50% of patients with sarcoidosis,²³ reflecting the conduction disease or arrhythmias commonly seen in cardiac involvement.

Chest radiography classically shows hilar lymphadenopathy and interstitial disease, and may show cardiomegaly, pericardial effusion, or left ventricular aneurysm.

Echocardiography is nonspecific for sarcoid disease, but granulomatous involvement and scar tissue of cardiac tissue may appear hyperechogenic, particularly in the ventricular septum or left ventricular free wall.²⁴

Angiography. Primary sarcoidosis rarely involves the coronary arteries,²⁵ so angiography is most useful in excluding the diagnosis of atherosclerotic coronary artery disease.

Radionuclide imaging with thallium 201 in patients with suspected cardiac sarcoidosis may be useful to suggest myocardial involvement and to exclude cardiac dysfunction secondary to coronary artery disease. Segmental areas with defective thallium 201 uptake correspond to fibrogranulomatous tissue. In resting images, the pattern may be similar to that seen in coronary artery disease. However, during exercise, perfusion defects increase in patients who have ischemia but actually decrease in those with cardiac sarcoidosis.²⁶

Nevertheless, some conclude that thallium scanning is too nonspecific for it to be used as a diagnostic or screening test.^27,28 The combined use of thallium 201 and gallium 67 may better detect cardiac sarcoidosis, as gallium is taken up in areas of active inflammation.

Positron-emission tomography (PET) with fluorodeoxyglucose F 18 (FDG), with the patient fasting, appears to be useful in detecting the early inflammation of cardiac sarcoidosis^29–34 and monitoring disease activity.^30,31 FDG is a glucose analogue that is taken up by granulomatous tissue in the myocardium.³⁴ The uptake in cardiac sarcoidosis is in a focal distribution.^30,31,34 The abnormal FDG uptake resolves with steroid treatment.^31,32

MRI has promise for diagnosing cardiac sarcoidosis. With gadolinium contrast, MRI has superior image resolution and can detect cardiac involvement early in its course.^{27,29,35–44}

Inflammation of the myocardium due to sarcoid involvement appears as focal zones of increased signal intensity on both T2-weighted and early gadolinium T1-weighted images. Late myocardial enhancement after gadolinium infusion is the most typical finding of cardiac sarcoidosis on MRI, and likely represents fibrogranulomatous tissue.²⁷ Delayed gadolinium enhancement is also seen in myocardial infarction but differs in its distribution.^1,35,45 Cardiac sarcoidosis most commonly affects the basal and lateral segments. In one study, the finding of delayed enhancement had a sensitivity of 100% and a specificity of 78%,^1,27 though it may not sufficiently differentiate active inflammation from scar.³⁰

Like FDG-PET, MRI has also been shown to be useful for monitoring treatment.^33,46 However, PET is more useful for follow-up in patients who receive a pacemaker or implantable cardioverter-defibrillator, in whom MRI is contraindicated. One case report²⁹ described using both delayed-enhancement MRI and FDG-PET to diagnose cardiac sarcoidosis.

TREATMENT

6. How is cardiac sarcoidosis currently treated?

• Implantable cardioverter-defibrillator
• Corticosteroids
• Heart transplantation
• All of the above
• None of the above

Corticosteroids

Corticosteroids are the mainstay of treatment of cardiac sarcoidosis, as they attenuate the characteristic inflammation and fibrosis of sarcoid granulomas. The goal is to prevent compromise of cardiac structure or function.⁴⁷ Although most of the supporting data are anecdotal, steroids have been shown to improve ventricular contractility,⁴⁸ arrhythmias,⁴⁹ and conduction abnormalities.⁵⁰ MRI and FDG-PET studies have shown cardiac lesions resolving after steroids were started.^31,45,46

The optimal dosage remains unknown. Initial doses of 30 to 60 mg daily, gradually tapered over 6 to 12 months to maintenance doses of 5 to 10 mg daily, have been effective.^45,51

Relapses are common and require vigilant monitoring.

Alternative agents such as cyclophosphamide (Cytoxan),⁵² methotrexate (Rheumatrex), ⁵³ and cyclosporine (Sandimmune)⁵⁴ can be given to patients whose disease does not respond to corticosteroids or who cannot tolerate their side effects.

Implantable cardioverter-defibrillator

Sudden death due to ventricular tachyarrhythmias or conduction block accounts for 30% to 65% of deaths in patients with cardiac sarcoidosis.¹⁰ The rates of recurrent ventricular tachycardia and sudden death are high, even with antiarrhythmic drug therapy.⁵⁵

Although experience with implantable cardiac defibrillators is limited in patients with cardiac sarcoidosis,^55–58 some have argued that they be strongly considered to prevent sudden cardiac death in this high-risk group.^57,58

Heart transplantation

The largest body of data on transplantation comes from the United Network for Organ Sharing database. In the 65 patients with cardiac sarcoidosis who underwent cardiac transplantation in the 18 years from October 1987 to September 2005, the 1-year post-transplant survival rate was 88%, which was better than in patients with all other diagnoses (85%). The 5-year survival rate was 80%.^59,60

Recurrence of sarcoidosis within the cardiac allograft and transmission of sarcoidosis from donor to recipient have both been documented after heart transplantation.^61,62

 

CAUSES OF DEATH

7. What is the most common cause of death in patients with cardiac sarcoidosis?

• Respiratory failure
• Conduction disturbances
• Progressive heart failure
• Ventricular tachyarrhythmias
• None of the above

The prognosis of symptomatic cardiac sarcoidosis is not well defined, owing to the variable extent and severity of the disease. The mortality rate in sarcoidosis without cardiac involvement is about 1% to 5% per year.^63,64 Cardiac involvement portends a worse prognosis, with a 55% survival rate at 5 years and 44% at 10 years.^17,65 Most patients in the reported series ultimately died of cardiac complications of sarcoidosis, including ventricular tachyarrhythmias, conduction disturbances, and progressive cardiomyopathy.^10,17

Since corticosteroids, pacemakers, and implantable cardioverter-defibrillators have begun to be used, the cause of death has shifted from sudden death to progressive heart failure.⁶⁶

CASE CONTINUED

While hospitalized, our patient had two episodes of nonsustained ventricular tachycardia (7 and 12 beats) on telemetry. Cardiac MRI showed a lesion in the basal septum most likely involving the left bundle and an area of lateral basilar involvement near the mitral annulus (Figure 2). Ventricular dyssynchrony was clearly evident on both echocardiography and MRI, with depressed left ventricular function (ejection fraction 28% on MRI, 35% on echocardiography).

Electrophysiologic testing revealed inducible monomorphic sustained ventricular tachycardia. The patient subsequently had a biventricular cardioverter-defibrillator implanted. He was started on an angiotensin-converting enzyme inhibitor and a beta-blocker for his heart failure. Further imaging of his chest and abdomen revealed lesions in his thyroid and liver. As of this writing, he is undergoing further workup. Because of active infection with Clostridium difficile, steroid therapy was deferred.

A 42-year-old man was working at his computer when he suddenly became disoriented and lightheaded, had difficulty concentrating, and could not move his right arm. He could walk without difficulty, but he had a tingling sensation in his right leg. He did not lose consciousness or have any associated palpitations, chest pain, shortness of breath, nausea, vomiting, headaches, or visual changes.

He called 911, and an ambulance arrived 15 minutes later. By that time his symptoms had started to resolve. Now, in the emergency department, his only residual symptom is mild numbness of his right arm and shoulder.

Until now he has been healthy except for a history of dyslipidemia. He takes no prescription or over-the-counter medications and has no drug allergies. He has smoked one pack of cigarettes daily for the past 28 years and also smokes marijuana several times each month. He drinks alcohol occasionally. His family has no history of stroke, premature coronary artery disease, or sudden cardiac death.

INITIAL EVALUATION

His heart rate is 88 beats per minute, blood pressure 142/82 mm Hg, and blood oxygen saturation 98% while breathing room air. He is alert and in no acute distress and answers questions appropriately.

His breathing sounds are normal, without crackles or wheezes. His heart has normal first and second sounds, a normal rate and rhythm, and no extra sounds or murmurs. His abdomen is normal. His extremities are warm and well perfused with normal peripheral pulses and no edema.

On neurologic examination, his cranial nerves and visual fields are normal, and his strength is normal in all muscle groups except for the right upper arm, which is slightly weaker than the left when tested against resistance. Reflexes and response to light touch and pinprick are normal.

His serum chemistry levels, renal function, and blood counts are normal. His total cholesterol level is 155 mg/dL, high-density lipoprotein cholesterol 38 mg/dL, low-density lipoprotein cholesterol 108 mg/dL, and triglycerides 1,286 mg/dL. Electrocardiography is normal with sinus rhythm at a rate of 74.

Magnetic resonance imaging (MRI) of the head and neck with magnetic resonance angiography (MRA) of the intracranial and extracranial vessels is performed. Diffusion-weighted images show a hyperintense lesion in the left insular cortex, consistent with an infarct in the distribution of a branch of the left middle cerebral artery. There is no intracranial hemorrhage. All intracranial and extracranial major vessels are patent, and no stenoses are seen.

DIFFERENTIAL DIAGNOSIS

1. Which is the most likely cause of this patient’s stroke?

• Vertebral or carotid atherosclerosis
• Cervical arterial dissection
• A hematologic disorder
• Cocaine abuse
• Cardiac embolism

Atherosclerosis

Although 85% of all strokes are ischemic, and most ischemic strokes are caused by occlusive atherosclerosis of large vessels, most ischemic strokes occur in patients older than 65 years. In patients younger than 55 years, only about 10% of strokes are caused by large-vessel atherosclerotic disease, thus lowering the initial probability that this is the cause of our patient’s stroke.¹ Furthermore, our patient’s MRA study showed no carotid artery stenoses, which effectively eliminates this as the cause of his stroke, as the diagnostic sensitivity of MRA for detecting carotid stenosis is approximately 97%.

Cervical arterial dissection

Cervical arterial dissection causes up to 20% of strokes in patients younger than 45 years.² Dissections usually involve the extracranial portion of the vessel, and involve the internal carotid arteries at least three times as often as the vertebral arteries. In many cases the dissection is preceded by mild neck trauma, which may be as minor as a vigorous cough or turning of the head.

Typical features of dissection include neck pain, headache, and Horner syndrome, followed minutes to hours later by symptoms of ocular or cerebral ischemia, usually a transient ischemic attack rather than a stroke. Neurologic symptoms are most commonly due to thrombosis at the dissection site with distal embolization. Inherited disorders that are associated with increased risk of cervical arterial dissection include Ehlers-Danlos syndrome type IV, Marfan syndrome, autosomal-dominant polycystic kidney disease, osteogenesis imperfecta type I, and fibromuscular dysplasia.³ MRA and computed tomographic angiography are the diagnostic tests of choice.

Our patient’s symptoms began suddenly, without a history of trauma or neck pain, making arterial dissection less likely as the cause of his stroke. No dissection was seen on MRA, which also minimizes its likelihood.⁴

 

 

Hematologic disorders

Many hematologic disorders are associated with ischemic stroke. The disorders most likely to cause ischemic stroke in patients younger than 45 years are antiphospholipid antibody syndrome, sickle cell anemia, and heparin-induced thrombocytopenia,⁵ which are associated with arterial thrombosis.

Most of the common hereditary hypercoagulable disorders, such as factor V Leiden/activated protein C resistance, the prothrombin gene mutation (G20210A), antithrombin III deficiency, protein C deficiency, and protein S deficiency, typically cause venous thrombosis much more often than they cause arterial thrombosis. Thus, the most typical presentations of stroke in these disorders are cerebral venous thrombosis or paradoxical embolic stroke due to a patent foramen ovale. Antithrombin III deficiency and protein C and protein S deficiency have been associated with arterial thrombosis, but so infrequently that their likelihood in this patient is extremely low.

Clues to the diagnosis of a hypercoagulable state include venous thrombosis in the past, recurrent fetal loss, thrombocytopenia, livedo reticularis, antiphospholipid antibody syndrome, and skin necrosis at the start of oral anticoagulant therapy.

Of importance: the relationship between hereditary hypercoagulable disorders and stroke is considerably weaker than their association with venous thrombosis. Several studies in clinical and general populations have failed to show an independent association between stroke and protein C deficiency, protein S deficiency, antithrombin III deficiency, factor V Leiden/activated protein C resistance, or the prothrombin G20210A mutation.^6–8 Therefore, most experts do not recommend screening all stroke patients for a hypercoagulable state—only those with a personal or family history of thrombosis or young patients with unexplained stroke.

Our patient does not have historical or clinical features that would suggest a specific hypercoagulable disorder, either acquired (eg, heparin-induced thrombocytopenia) or inherited. A laboratory workup for a hypercoagulable disorder would likely be of little value in determining the cause of his stroke, and even if a hereditary disorder were identified it would be difficult to determine causation. However, if no other explanation for his stroke can be found during the workup, one could consider testing for proteins C and S, antithrombin III, activated protein C resistance (and factor V Leiden if screening for activated protein C resistance is positive), prothrombin G20210A, fibrinogen, homocysteine, D-dimers, and antiphospholipid antibodies.

Cocaine abuse

Another important cause of ischemic stroke is the use of sympathomimetic drugs such as cocaine or amphetamines. The strongest association is with cocaine, which has been seen in case series to cause cerebral vasoconstriction in a dose-dependent manner. Vasoconstriction is also related to a longer duration of cocaine use.⁹ Several case-control studies have found that the risk of stroke is 4.5 to 6.5 times higher in drug abusers than in controls, and that use of catecholamines or cocaine alone was associated with a significantly increased risk of stroke.^10,11

It is certainly advisable to ask about the use of illicit drugs and to send serum and urine samples for appropriate drug screening in young stroke patients, particularly if another cause cannot be found or if drug use is suspected.¹²

Cardiac embolism

Cardiac embolism is the most likely cause of the stroke in this patient. Up to 20% of the 500,000 strokes that occur annually in the United States are of cardiac embolic origin,¹³ and the prevalence is even higher in younger patients. In a registry of 428 strokes in patients 15 to 44 years of age, a cardiac source of embolism was the cause in 31.8%.¹⁴

Cardiac causes of embolization (Figure 1) can be categorized as:

 

• Masses, which include atherosclerotic plaques, cardiac tumors, and infective and noninfective valvular vegetations
• Passageways for paradoxical embolism, such as a patent foramen ovale or atrial septal defect (Figure 2)
• Stasis in the left atrium or left ventricle, with a resulting propensity for thrombosis.

Of these, the most common are left atrial and left ventricular thrombi and aortic atherosclerosis.¹⁵

Atrial thrombus is most often seen in patients with atrial fibrillation, mitral stenosis, or dilated cardiomyopathy. Echocardiography of the left atrium in patients with these conditions often reveals spontaneous echo contrast that resembles swirling “smoke,” which is thought to be produced by red blood cell aggregation due to blood stasis. This sign is strongly associated with left atrial thrombi.

Left ventricular thrombosis is one of the most common complications of myocardial infarction and is caused by blood stasis in regions of the ventricle in which the myocardium is hypokinetic or akinetic.

We cannot assume, however, that a potential cardioembolic source seen on echocardiography is the cause of a given patient’s stroke. The evidence proving a causal relationship between most potential cardiac embolic sources and stroke is less than robust. Most of the published data are from nonrandomized studies or case series, and there are no large, prospective studies available to clearly prove that a given cardioembolic source is directly related to embolic stroke.¹⁶

This being said, most studies have found high prevalence rates of cardioembolic sources in patients with embolic stroke, which suggests that a causative relationship may exist. However, many of these findings also have a relatively high prevalence among the general population without stroke, raising the possibility that the finding could be incidental and unrelated. Examples are patent foramen ovale, which exists in 27% of adults,¹⁷ and aortic arch atheroma, which is common in the elderly.

In the end, when the only potential source of embolism that can be found is in the heart (as is often the case in younger patients), the probability is much greater that it is indeed the cause of the stroke. The lack of direct evidence linking many sources of cardioembolism to stroke emphasizes the need for a thorough investigation of all possible causes of stroke.

 

DIAGNOSTIC EVALUATION

2. Which is the best study to evaluate for a cardiac embolic source in this patient?

• Transthoracic echocardiography (TTE)
• Transesophageal echocardiography (TEE)
• Transcranial Doppler ultrasonography
• Electrocardiography

The study of choice in this patient is TEE. Overall, TEE is better than TTE in identifying a cardiac source of embolism,^18,19 mainly because the images are obtained from a probe in the esophagus, which is in close proximity to the heart, so that there is little additional soft tissue and bone between the probe and cardiac structures. In addition, higher-frequency probes can be used. Both of these result in ultrasonographic images with much greater spatial resolution than can be obtained with a transthoracic study.¹⁵

In a case series,²⁰ TEE identified a potential cardiac source of embolism in 45 (57%) of 79 patients with cryptogenic stroke, compared with only 12 (15%) with TTE.

The main limitation of TEE is that it does not show the left ventricular apex very well, making an accurate assessment of left ventricular function or identification of a left ventricular apical thrombus much less likely.

In patients who lack evidence of atherosclerotic cerebrovascular disease, specific findings on history or physical examination could increase the chances of identifying an embolic source, such as left ventricular thrombus, on TTE. These findings could include a history of a myocardial infarction, congestive heart failure, left ventricular dysfunction, endocarditis, rheumatic heart disease, a prosthetic valve, or atrial fibrillation or flutter. TTE by itself is considered sufficient for making the diagnosis of mitral stenosis, left ventricular aneurysm, dilated cardiomyopathy, left ventricular thrombus, and mitral valve prolapse with myxomatous degeneration of the leaflets.

However, in patients without signs or symptoms of cardiac disease, the diagnostic value of TTE is significantly less. Several studies have demonstrated that in patients without evidence of cardiac disease, TTE identifies the source of embolism less than 10% of the time.²¹ Some series even suggest that the yield may be less than 1%.²² TEE has the advantage of being able to diagnose the above disorders and of having a higher sensitivity for identifying potential sources that may be missed by TTE, such as left atrial or left atrial appendage thrombus, aortic arch atheroma, patent foramen ovale, atrial septal aneurysm, or spontaneous echo contrast. It should be remembered, however, that TEE is a semi-invasive procedure that carries the risks of both the procedure and the sedation, eg, bronchospasm, hypoxia, arrhythmias, upper gastrointestinal trauma, and bleeding.²³

Further clouding the decision are recent advances in TTE technology, such as contrast TTE with second harmonic imaging, which enhances the ability of TTE to identify potential sources of stroke such as patent foramen ovale nearly to the level of TEE.²⁴

Unfortunately, guidelines from professional societies do not offer assistance on the best diagnostic approach. Current guidelines from the American Heart Association, American College of Cardiology, and American Society of Echocardiography do give echocardiography a class I indication in younger patients (< 45 years old) with cerebrovascular events or older patients (> 45 years old) with stroke without evidence of cerebrovascular disease or other obvious causes. However, there is no official recommendation on whether to choose TTE, TEE, or both studies.¹⁶ Given the multiple causes of cardioembolism and the variety of clinical factors that could influence the decision to choose a certain echo study, this decision is appropriately left to the individual physician.

A reasonable, evidence-based diagnostic approach in young stroke patients is to proceed to TEE when routine TTE and electrocardiography are unrevealing.²⁵ In reality, this is the practice followed in most centers, including ours. Although TTE has a lower diagnostic yield in patients without symptoms, it has the advantages of being readily available in most centers, being noninvasive, and providing complementary information to TEE even when TTE does not reveal a potential cause of stroke.

As for the other studies:

Electrocardiography is valuable in identifying potential cardioembolic causes of stroke such as atrial fibrillation, left ventricular aneurysm, or myocardial infarction, but it is insufficient by itself to assess for many other potential sources of cardioembolism.

Transcranial Doppler ultrasonography is very sensitive for detecting patent foramen ovale and other right-to-left shunts that could be sources of cardioembolism. In this test, microbubbles from agitated saline are injected into the venous circulation and are detected in the cerebral arteries after passing through the shunt. It has no utility in identifying the other possibilities discussed above, nor can it discriminate whether these shunts are intra-cardiac or extracardiac.

Case continued

The patient undergoes TTE, which shows normal left ventricular size, wall thickness, and systolic function. His right ventricular function is normal, as are his left and right atrial size. Valvular function is normal, and no right-to-left interatrial shunt is detected with the use of agitated saline contrast.

The patient then undergoes TEE, which reveals a 9- by 8-mm mobile soft-tissue mass attached to the aortic side of the aortic valve at the junction of the right and left coronary cusps (Figure 3). There is trivial aortic insufficiency, and the rest of the aorta appears normal. This lesion is consistent with a valvular papillary fibroelastoma.

 

MANAGEMENT

3. Which is the most appropriate way to manage the lesion?

• Surgical resection
• Periodic echocardiographic follow-up
• Anticoagulation and periodic echocardiographic follow-up

Cardiac papillary fibroelastomas are rare benign primary tumors of the heart. The true incidence is unknown because, when small, they can be asymptomatic and easily overlooked on gross examination. In adults, they are the second most common primary cardiac tumors, next to atrial myxoma.²⁶

These tumors primarily affect the valves (most often the aortic valve), and consist of a small, highly papillary, avascular tumor covered by a single layer of endothelium, containing variable amounts of fine elastic fibers arranged around a central hyaline stroma (Figure 4).²⁷ Most of the tumors are sessile, while a few are attached to the valve by a short stalk.

The histogenesis is not known, but the mean age at which they are detected is approximately 60 years, and most of the patients are men, likely because most of these tumors are found incidentally during echocardiography, open heart surgery, or autopsy.²⁸

Most patients with cardiac papillary fibroelastomas have no symptoms; however, those who do have symptoms usually experience valve obstruction or embolization of tumor fragments, leading to stroke, myocardial infarction, or sudden death. Further increasing the risk of embolism, thrombus has been reported on the surface of some tumors, supporting the use of anticoagulation in patients who have experienced embolic phenomena.²⁹

A case review of 725 patients with these tumors²⁷ found that tumor mobility and location on the aortic valve were univariate predictors of tumor-related death and of nonfatal embolism. The only independent predictor of tumor-related death or nonfatal embolization was tumor mobility.

Surgical resection of the tumor is curative, and no recurrences have been reported, although the longest follow-up period has been 11 years.

Although no data exist to support the practice, patients with nonmobile or nonaortic valve tumors could be managed with anticoagulation and periodic echocardiographic follow-up until the tumor becomes mobile or symptomatic, but such a conservative strategy would seem inappropriate for our patient. His tumor is both mobile and located on the aortic valve, putting him at risk of death, and he has already experienced an embolic complication. Therefore, his lesion should be surgically resected.

Case continued

The patient receives anticoagulation therapy with subcutaneous enoxaparin (Lovenox) and warfarin (Coumadin). He undergoes successful surgical resection of the tumor without complication and is discharged to home on hospital day 5.

TAKE-HOME POINTS

The potential causes of stroke in patients younger than age 45 differ significantly from those in older patients. Cardiac embolism is the most frequent cause of stroke in young patients and is most often from left atrial or ventricular thrombus or from aortic atheroma.

In young patients, TEE is superior to TTE in identifying a specific source of cardiac embolism, particularly when clues from the history or physical examination are lacking and the preliminary diagnostic workup fails to identify the cause of the stroke.

Our patient’s history, physical examination, MRI, MRA, electrocardiography, and TTE all failed to disclose a probable cause of his stroke. Appropriately, TEE was performed, which confirmed the diagnosis of cardiac papillary fibroelastoma, a rare and benign primary tumor of the heart with the potential for disastrous consequences.

A 42-year-old man was working at his computer when he suddenly became disoriented and lightheaded, had difficulty concentrating, and could not move his right arm. He could walk without difficulty, but he had a tingling sensation in his right leg. He did not lose consciousness or have any associated palpitations, chest pain, shortness of breath, nausea, vomiting, headaches, or visual changes.

He called 911, and an ambulance arrived 15 minutes later. By that time his symptoms had started to resolve. Now, in the emergency department, his only residual symptom is mild numbness of his right arm and shoulder.

Until now he has been healthy except for a history of dyslipidemia. He takes no prescription or over-the-counter medications and has no drug allergies. He has smoked one pack of cigarettes daily for the past 28 years and also smokes marijuana several times each month. He drinks alcohol occasionally. His family has no history of stroke, premature coronary artery disease, or sudden cardiac death.

INITIAL EVALUATION

His heart rate is 88 beats per minute, blood pressure 142/82 mm Hg, and blood oxygen saturation 98% while breathing room air. He is alert and in no acute distress and answers questions appropriately.

His breathing sounds are normal, without crackles or wheezes. His heart has normal first and second sounds, a normal rate and rhythm, and no extra sounds or murmurs. His abdomen is normal. His extremities are warm and well perfused with normal peripheral pulses and no edema.

On neurologic examination, his cranial nerves and visual fields are normal, and his strength is normal in all muscle groups except for the right upper arm, which is slightly weaker than the left when tested against resistance. Reflexes and response to light touch and pinprick are normal.

His serum chemistry levels, renal function, and blood counts are normal. His total cholesterol level is 155 mg/dL, high-density lipoprotein cholesterol 38 mg/dL, low-density lipoprotein cholesterol 108 mg/dL, and triglycerides 1,286 mg/dL. Electrocardiography is normal with sinus rhythm at a rate of 74.

Magnetic resonance imaging (MRI) of the head and neck with magnetic resonance angiography (MRA) of the intracranial and extracranial vessels is performed. Diffusion-weighted images show a hyperintense lesion in the left insular cortex, consistent with an infarct in the distribution of a branch of the left middle cerebral artery. There is no intracranial hemorrhage. All intracranial and extracranial major vessels are patent, and no stenoses are seen.

DIFFERENTIAL DIAGNOSIS

1. Which is the most likely cause of this patient’s stroke?

• Vertebral or carotid atherosclerosis
• Cervical arterial dissection
• A hematologic disorder
• Cocaine abuse
• Cardiac embolism

Atherosclerosis

Although 85% of all strokes are ischemic, and most ischemic strokes are caused by occlusive atherosclerosis of large vessels, most ischemic strokes occur in patients older than 65 years. In patients younger than 55 years, only about 10% of strokes are caused by large-vessel atherosclerotic disease, thus lowering the initial probability that this is the cause of our patient’s stroke.¹ Furthermore, our patient’s MRA study showed no carotid artery stenoses, which effectively eliminates this as the cause of his stroke, as the diagnostic sensitivity of MRA for detecting carotid stenosis is approximately 97%.

Cervical arterial dissection

Cervical arterial dissection causes up to 20% of strokes in patients younger than 45 years.² Dissections usually involve the extracranial portion of the vessel, and involve the internal carotid arteries at least three times as often as the vertebral arteries. In many cases the dissection is preceded by mild neck trauma, which may be as minor as a vigorous cough or turning of the head.

Typical features of dissection include neck pain, headache, and Horner syndrome, followed minutes to hours later by symptoms of ocular or cerebral ischemia, usually a transient ischemic attack rather than a stroke. Neurologic symptoms are most commonly due to thrombosis at the dissection site with distal embolization. Inherited disorders that are associated with increased risk of cervical arterial dissection include Ehlers-Danlos syndrome type IV, Marfan syndrome, autosomal-dominant polycystic kidney disease, osteogenesis imperfecta type I, and fibromuscular dysplasia.³ MRA and computed tomographic angiography are the diagnostic tests of choice.

Our patient’s symptoms began suddenly, without a history of trauma or neck pain, making arterial dissection less likely as the cause of his stroke. No dissection was seen on MRA, which also minimizes its likelihood.⁴

 

 

Hematologic disorders

Many hematologic disorders are associated with ischemic stroke. The disorders most likely to cause ischemic stroke in patients younger than 45 years are antiphospholipid antibody syndrome, sickle cell anemia, and heparin-induced thrombocytopenia,⁵ which are associated with arterial thrombosis.

Most of the common hereditary hypercoagulable disorders, such as factor V Leiden/activated protein C resistance, the prothrombin gene mutation (G20210A), antithrombin III deficiency, protein C deficiency, and protein S deficiency, typically cause venous thrombosis much more often than they cause arterial thrombosis. Thus, the most typical presentations of stroke in these disorders are cerebral venous thrombosis or paradoxical embolic stroke due to a patent foramen ovale. Antithrombin III deficiency and protein C and protein S deficiency have been associated with arterial thrombosis, but so infrequently that their likelihood in this patient is extremely low.

Clues to the diagnosis of a hypercoagulable state include venous thrombosis in the past, recurrent fetal loss, thrombocytopenia, livedo reticularis, antiphospholipid antibody syndrome, and skin necrosis at the start of oral anticoagulant therapy.

Of importance: the relationship between hereditary hypercoagulable disorders and stroke is considerably weaker than their association with venous thrombosis. Several studies in clinical and general populations have failed to show an independent association between stroke and protein C deficiency, protein S deficiency, antithrombin III deficiency, factor V Leiden/activated protein C resistance, or the prothrombin G20210A mutation.^6–8 Therefore, most experts do not recommend screening all stroke patients for a hypercoagulable state—only those with a personal or family history of thrombosis or young patients with unexplained stroke.

Our patient does not have historical or clinical features that would suggest a specific hypercoagulable disorder, either acquired (eg, heparin-induced thrombocytopenia) or inherited. A laboratory workup for a hypercoagulable disorder would likely be of little value in determining the cause of his stroke, and even if a hereditary disorder were identified it would be difficult to determine causation. However, if no other explanation for his stroke can be found during the workup, one could consider testing for proteins C and S, antithrombin III, activated protein C resistance (and factor V Leiden if screening for activated protein C resistance is positive), prothrombin G20210A, fibrinogen, homocysteine, D-dimers, and antiphospholipid antibodies.

Cocaine abuse

Another important cause of ischemic stroke is the use of sympathomimetic drugs such as cocaine or amphetamines. The strongest association is with cocaine, which has been seen in case series to cause cerebral vasoconstriction in a dose-dependent manner. Vasoconstriction is also related to a longer duration of cocaine use.⁹ Several case-control studies have found that the risk of stroke is 4.5 to 6.5 times higher in drug abusers than in controls, and that use of catecholamines or cocaine alone was associated with a significantly increased risk of stroke.^10,11

It is certainly advisable to ask about the use of illicit drugs and to send serum and urine samples for appropriate drug screening in young stroke patients, particularly if another cause cannot be found or if drug use is suspected.¹²

Cardiac embolism

Cardiac embolism is the most likely cause of the stroke in this patient. Up to 20% of the 500,000 strokes that occur annually in the United States are of cardiac embolic origin,¹³ and the prevalence is even higher in younger patients. In a registry of 428 strokes in patients 15 to 44 years of age, a cardiac source of embolism was the cause in 31.8%.¹⁴

Cardiac causes of embolization (Figure 1) can be categorized as:

 

• Masses, which include atherosclerotic plaques, cardiac tumors, and infective and noninfective valvular vegetations
• Passageways for paradoxical embolism, such as a patent foramen ovale or atrial septal defect (Figure 2)
• Stasis in the left atrium or left ventricle, with a resulting propensity for thrombosis.

Of these, the most common are left atrial and left ventricular thrombi and aortic atherosclerosis.¹⁵

Atrial thrombus is most often seen in patients with atrial fibrillation, mitral stenosis, or dilated cardiomyopathy. Echocardiography of the left atrium in patients with these conditions often reveals spontaneous echo contrast that resembles swirling “smoke,” which is thought to be produced by red blood cell aggregation due to blood stasis. This sign is strongly associated with left atrial thrombi.

Left ventricular thrombosis is one of the most common complications of myocardial infarction and is caused by blood stasis in regions of the ventricle in which the myocardium is hypokinetic or akinetic.

We cannot assume, however, that a potential cardioembolic source seen on echocardiography is the cause of a given patient’s stroke. The evidence proving a causal relationship between most potential cardiac embolic sources and stroke is less than robust. Most of the published data are from nonrandomized studies or case series, and there are no large, prospective studies available to clearly prove that a given cardioembolic source is directly related to embolic stroke.¹⁶

This being said, most studies have found high prevalence rates of cardioembolic sources in patients with embolic stroke, which suggests that a causative relationship may exist. However, many of these findings also have a relatively high prevalence among the general population without stroke, raising the possibility that the finding could be incidental and unrelated. Examples are patent foramen ovale, which exists in 27% of adults,¹⁷ and aortic arch atheroma, which is common in the elderly.

In the end, when the only potential source of embolism that can be found is in the heart (as is often the case in younger patients), the probability is much greater that it is indeed the cause of the stroke. The lack of direct evidence linking many sources of cardioembolism to stroke emphasizes the need for a thorough investigation of all possible causes of stroke.

 

DIAGNOSTIC EVALUATION

2. Which is the best study to evaluate for a cardiac embolic source in this patient?

• Transthoracic echocardiography (TTE)
• Transesophageal echocardiography (TEE)
• Transcranial Doppler ultrasonography
• Electrocardiography

The study of choice in this patient is TEE. Overall, TEE is better than TTE in identifying a cardiac source of embolism,^18,19 mainly because the images are obtained from a probe in the esophagus, which is in close proximity to the heart, so that there is little additional soft tissue and bone between the probe and cardiac structures. In addition, higher-frequency probes can be used. Both of these result in ultrasonographic images with much greater spatial resolution than can be obtained with a transthoracic study.¹⁵

In a case series,²⁰ TEE identified a potential cardiac source of embolism in 45 (57%) of 79 patients with cryptogenic stroke, compared with only 12 (15%) with TTE.

The main limitation of TEE is that it does not show the left ventricular apex very well, making an accurate assessment of left ventricular function or identification of a left ventricular apical thrombus much less likely.

In patients who lack evidence of atherosclerotic cerebrovascular disease, specific findings on history or physical examination could increase the chances of identifying an embolic source, such as left ventricular thrombus, on TTE. These findings could include a history of a myocardial infarction, congestive heart failure, left ventricular dysfunction, endocarditis, rheumatic heart disease, a prosthetic valve, or atrial fibrillation or flutter. TTE by itself is considered sufficient for making the diagnosis of mitral stenosis, left ventricular aneurysm, dilated cardiomyopathy, left ventricular thrombus, and mitral valve prolapse with myxomatous degeneration of the leaflets.

However, in patients without signs or symptoms of cardiac disease, the diagnostic value of TTE is significantly less. Several studies have demonstrated that in patients without evidence of cardiac disease, TTE identifies the source of embolism less than 10% of the time.²¹ Some series even suggest that the yield may be less than 1%.²² TEE has the advantage of being able to diagnose the above disorders and of having a higher sensitivity for identifying potential sources that may be missed by TTE, such as left atrial or left atrial appendage thrombus, aortic arch atheroma, patent foramen ovale, atrial septal aneurysm, or spontaneous echo contrast. It should be remembered, however, that TEE is a semi-invasive procedure that carries the risks of both the procedure and the sedation, eg, bronchospasm, hypoxia, arrhythmias, upper gastrointestinal trauma, and bleeding.²³

Further clouding the decision are recent advances in TTE technology, such as contrast TTE with second harmonic imaging, which enhances the ability of TTE to identify potential sources of stroke such as patent foramen ovale nearly to the level of TEE.²⁴

Unfortunately, guidelines from professional societies do not offer assistance on the best diagnostic approach. Current guidelines from the American Heart Association, American College of Cardiology, and American Society of Echocardiography do give echocardiography a class I indication in younger patients (< 45 years old) with cerebrovascular events or older patients (> 45 years old) with stroke without evidence of cerebrovascular disease or other obvious causes. However, there is no official recommendation on whether to choose TTE, TEE, or both studies.¹⁶ Given the multiple causes of cardioembolism and the variety of clinical factors that could influence the decision to choose a certain echo study, this decision is appropriately left to the individual physician.

A reasonable, evidence-based diagnostic approach in young stroke patients is to proceed to TEE when routine TTE and electrocardiography are unrevealing.²⁵ In reality, this is the practice followed in most centers, including ours. Although TTE has a lower diagnostic yield in patients without symptoms, it has the advantages of being readily available in most centers, being noninvasive, and providing complementary information to TEE even when TTE does not reveal a potential cause of stroke.

As for the other studies:

Electrocardiography is valuable in identifying potential cardioembolic causes of stroke such as atrial fibrillation, left ventricular aneurysm, or myocardial infarction, but it is insufficient by itself to assess for many other potential sources of cardioembolism.

Transcranial Doppler ultrasonography is very sensitive for detecting patent foramen ovale and other right-to-left shunts that could be sources of cardioembolism. In this test, microbubbles from agitated saline are injected into the venous circulation and are detected in the cerebral arteries after passing through the shunt. It has no utility in identifying the other possibilities discussed above, nor can it discriminate whether these shunts are intra-cardiac or extracardiac.

Case continued

The patient undergoes TTE, which shows normal left ventricular size, wall thickness, and systolic function. His right ventricular function is normal, as are his left and right atrial size. Valvular function is normal, and no right-to-left interatrial shunt is detected with the use of agitated saline contrast.

The patient then undergoes TEE, which reveals a 9- by 8-mm mobile soft-tissue mass attached to the aortic side of the aortic valve at the junction of the right and left coronary cusps (Figure 3). There is trivial aortic insufficiency, and the rest of the aorta appears normal. This lesion is consistent with a valvular papillary fibroelastoma.

 

MANAGEMENT

3. Which is the most appropriate way to manage the lesion?

• Surgical resection
• Periodic echocardiographic follow-up
• Anticoagulation and periodic echocardiographic follow-up

Cardiac papillary fibroelastomas are rare benign primary tumors of the heart. The true incidence is unknown because, when small, they can be asymptomatic and easily overlooked on gross examination. In adults, they are the second most common primary cardiac tumors, next to atrial myxoma.²⁶

These tumors primarily affect the valves (most often the aortic valve), and consist of a small, highly papillary, avascular tumor covered by a single layer of endothelium, containing variable amounts of fine elastic fibers arranged around a central hyaline stroma (Figure 4).²⁷ Most of the tumors are sessile, while a few are attached to the valve by a short stalk.

The histogenesis is not known, but the mean age at which they are detected is approximately 60 years, and most of the patients are men, likely because most of these tumors are found incidentally during echocardiography, open heart surgery, or autopsy.²⁸

Most patients with cardiac papillary fibroelastomas have no symptoms; however, those who do have symptoms usually experience valve obstruction or embolization of tumor fragments, leading to stroke, myocardial infarction, or sudden death. Further increasing the risk of embolism, thrombus has been reported on the surface of some tumors, supporting the use of anticoagulation in patients who have experienced embolic phenomena.²⁹

A case review of 725 patients with these tumors²⁷ found that tumor mobility and location on the aortic valve were univariate predictors of tumor-related death and of nonfatal embolism. The only independent predictor of tumor-related death or nonfatal embolization was tumor mobility.

Surgical resection of the tumor is curative, and no recurrences have been reported, although the longest follow-up period has been 11 years.

Although no data exist to support the practice, patients with nonmobile or nonaortic valve tumors could be managed with anticoagulation and periodic echocardiographic follow-up until the tumor becomes mobile or symptomatic, but such a conservative strategy would seem inappropriate for our patient. His tumor is both mobile and located on the aortic valve, putting him at risk of death, and he has already experienced an embolic complication. Therefore, his lesion should be surgically resected.

Case continued

The patient receives anticoagulation therapy with subcutaneous enoxaparin (Lovenox) and warfarin (Coumadin). He undergoes successful surgical resection of the tumor without complication and is discharged to home on hospital day 5.

TAKE-HOME POINTS

The potential causes of stroke in patients younger than age 45 differ significantly from those in older patients. Cardiac embolism is the most frequent cause of stroke in young patients and is most often from left atrial or ventricular thrombus or from aortic atheroma.

In young patients, TEE is superior to TTE in identifying a specific source of cardiac embolism, particularly when clues from the history or physical examination are lacking and the preliminary diagnostic workup fails to identify the cause of the stroke.

Our patient’s history, physical examination, MRI, MRA, electrocardiography, and TTE all failed to disclose a probable cause of his stroke. Appropriately, TEE was performed, which confirmed the diagnosis of cardiac papillary fibroelastoma, a rare and benign primary tumor of the heart with the potential for disastrous consequences.

A 42-year-old man was working at his computer when he suddenly became disoriented and lightheaded, had difficulty concentrating, and could not move his right arm. He could walk without difficulty, but he had a tingling sensation in his right leg. He did not lose consciousness or have any associated palpitations, chest pain, shortness of breath, nausea, vomiting, headaches, or visual changes.

He called 911, and an ambulance arrived 15 minutes later. By that time his symptoms had started to resolve. Now, in the emergency department, his only residual symptom is mild numbness of his right arm and shoulder.

Until now he has been healthy except for a history of dyslipidemia. He takes no prescription or over-the-counter medications and has no drug allergies. He has smoked one pack of cigarettes daily for the past 28 years and also smokes marijuana several times each month. He drinks alcohol occasionally. His family has no history of stroke, premature coronary artery disease, or sudden cardiac death.

INITIAL EVALUATION

His heart rate is 88 beats per minute, blood pressure 142/82 mm Hg, and blood oxygen saturation 98% while breathing room air. He is alert and in no acute distress and answers questions appropriately.

His breathing sounds are normal, without crackles or wheezes. His heart has normal first and second sounds, a normal rate and rhythm, and no extra sounds or murmurs. His abdomen is normal. His extremities are warm and well perfused with normal peripheral pulses and no edema.

On neurologic examination, his cranial nerves and visual fields are normal, and his strength is normal in all muscle groups except for the right upper arm, which is slightly weaker than the left when tested against resistance. Reflexes and response to light touch and pinprick are normal.

His serum chemistry levels, renal function, and blood counts are normal. His total cholesterol level is 155 mg/dL, high-density lipoprotein cholesterol 38 mg/dL, low-density lipoprotein cholesterol 108 mg/dL, and triglycerides 1,286 mg/dL. Electrocardiography is normal with sinus rhythm at a rate of 74.

Magnetic resonance imaging (MRI) of the head and neck with magnetic resonance angiography (MRA) of the intracranial and extracranial vessels is performed. Diffusion-weighted images show a hyperintense lesion in the left insular cortex, consistent with an infarct in the distribution of a branch of the left middle cerebral artery. There is no intracranial hemorrhage. All intracranial and extracranial major vessels are patent, and no stenoses are seen.

DIFFERENTIAL DIAGNOSIS

1. Which is the most likely cause of this patient’s stroke?

• Vertebral or carotid atherosclerosis
• Cervical arterial dissection
• A hematologic disorder
• Cocaine abuse
• Cardiac embolism

Atherosclerosis

Although 85% of all strokes are ischemic, and most ischemic strokes are caused by occlusive atherosclerosis of large vessels, most ischemic strokes occur in patients older than 65 years. In patients younger than 55 years, only about 10% of strokes are caused by large-vessel atherosclerotic disease, thus lowering the initial probability that this is the cause of our patient’s stroke.¹ Furthermore, our patient’s MRA study showed no carotid artery stenoses, which effectively eliminates this as the cause of his stroke, as the diagnostic sensitivity of MRA for detecting carotid stenosis is approximately 97%.

Cervical arterial dissection

Cervical arterial dissection causes up to 20% of strokes in patients younger than 45 years.² Dissections usually involve the extracranial portion of the vessel, and involve the internal carotid arteries at least three times as often as the vertebral arteries. In many cases the dissection is preceded by mild neck trauma, which may be as minor as a vigorous cough or turning of the head.

Typical features of dissection include neck pain, headache, and Horner syndrome, followed minutes to hours later by symptoms of ocular or cerebral ischemia, usually a transient ischemic attack rather than a stroke. Neurologic symptoms are most commonly due to thrombosis at the dissection site with distal embolization. Inherited disorders that are associated with increased risk of cervical arterial dissection include Ehlers-Danlos syndrome type IV, Marfan syndrome, autosomal-dominant polycystic kidney disease, osteogenesis imperfecta type I, and fibromuscular dysplasia.³ MRA and computed tomographic angiography are the diagnostic tests of choice.

Our patient’s symptoms began suddenly, without a history of trauma or neck pain, making arterial dissection less likely as the cause of his stroke. No dissection was seen on MRA, which also minimizes its likelihood.⁴

 

 

Hematologic disorders

Many hematologic disorders are associated with ischemic stroke. The disorders most likely to cause ischemic stroke in patients younger than 45 years are antiphospholipid antibody syndrome, sickle cell anemia, and heparin-induced thrombocytopenia,⁵ which are associated with arterial thrombosis.

Most of the common hereditary hypercoagulable disorders, such as factor V Leiden/activated protein C resistance, the prothrombin gene mutation (G20210A), antithrombin III deficiency, protein C deficiency, and protein S deficiency, typically cause venous thrombosis much more often than they cause arterial thrombosis. Thus, the most typical presentations of stroke in these disorders are cerebral venous thrombosis or paradoxical embolic stroke due to a patent foramen ovale. Antithrombin III deficiency and protein C and protein S deficiency have been associated with arterial thrombosis, but so infrequently that their likelihood in this patient is extremely low.

Clues to the diagnosis of a hypercoagulable state include venous thrombosis in the past, recurrent fetal loss, thrombocytopenia, livedo reticularis, antiphospholipid antibody syndrome, and skin necrosis at the start of oral anticoagulant therapy.

Of importance: the relationship between hereditary hypercoagulable disorders and stroke is considerably weaker than their association with venous thrombosis. Several studies in clinical and general populations have failed to show an independent association between stroke and protein C deficiency, protein S deficiency, antithrombin III deficiency, factor V Leiden/activated protein C resistance, or the prothrombin G20210A mutation.^6–8 Therefore, most experts do not recommend screening all stroke patients for a hypercoagulable state—only those with a personal or family history of thrombosis or young patients with unexplained stroke.

Our patient does not have historical or clinical features that would suggest a specific hypercoagulable disorder, either acquired (eg, heparin-induced thrombocytopenia) or inherited. A laboratory workup for a hypercoagulable disorder would likely be of little value in determining the cause of his stroke, and even if a hereditary disorder were identified it would be difficult to determine causation. However, if no other explanation for his stroke can be found during the workup, one could consider testing for proteins C and S, antithrombin III, activated protein C resistance (and factor V Leiden if screening for activated protein C resistance is positive), prothrombin G20210A, fibrinogen, homocysteine, D-dimers, and antiphospholipid antibodies.

Cocaine abuse

Another important cause of ischemic stroke is the use of sympathomimetic drugs such as cocaine or amphetamines. The strongest association is with cocaine, which has been seen in case series to cause cerebral vasoconstriction in a dose-dependent manner. Vasoconstriction is also related to a longer duration of cocaine use.⁹ Several case-control studies have found that the risk of stroke is 4.5 to 6.5 times higher in drug abusers than in controls, and that use of catecholamines or cocaine alone was associated with a significantly increased risk of stroke.^10,11

It is certainly advisable to ask about the use of illicit drugs and to send serum and urine samples for appropriate drug screening in young stroke patients, particularly if another cause cannot be found or if drug use is suspected.¹²

Cardiac embolism

Cardiac embolism is the most likely cause of the stroke in this patient. Up to 20% of the 500,000 strokes that occur annually in the United States are of cardiac embolic origin,¹³ and the prevalence is even higher in younger patients. In a registry of 428 strokes in patients 15 to 44 years of age, a cardiac source of embolism was the cause in 31.8%.¹⁴

Cardiac causes of embolization (Figure 1) can be categorized as:

 

• Masses, which include atherosclerotic plaques, cardiac tumors, and infective and noninfective valvular vegetations
• Passageways for paradoxical embolism, such as a patent foramen ovale or atrial septal defect (Figure 2)
• Stasis in the left atrium or left ventricle, with a resulting propensity for thrombosis.

Of these, the most common are left atrial and left ventricular thrombi and aortic atherosclerosis.¹⁵

Atrial thrombus is most often seen in patients with atrial fibrillation, mitral stenosis, or dilated cardiomyopathy. Echocardiography of the left atrium in patients with these conditions often reveals spontaneous echo contrast that resembles swirling “smoke,” which is thought to be produced by red blood cell aggregation due to blood stasis. This sign is strongly associated with left atrial thrombi.

Left ventricular thrombosis is one of the most common complications of myocardial infarction and is caused by blood stasis in regions of the ventricle in which the myocardium is hypokinetic or akinetic.

We cannot assume, however, that a potential cardioembolic source seen on echocardiography is the cause of a given patient’s stroke. The evidence proving a causal relationship between most potential cardiac embolic sources and stroke is less than robust. Most of the published data are from nonrandomized studies or case series, and there are no large, prospective studies available to clearly prove that a given cardioembolic source is directly related to embolic stroke.¹⁶

This being said, most studies have found high prevalence rates of cardioembolic sources in patients with embolic stroke, which suggests that a causative relationship may exist. However, many of these findings also have a relatively high prevalence among the general population without stroke, raising the possibility that the finding could be incidental and unrelated. Examples are patent foramen ovale, which exists in 27% of adults,¹⁷ and aortic arch atheroma, which is common in the elderly.

In the end, when the only potential source of embolism that can be found is in the heart (as is often the case in younger patients), the probability is much greater that it is indeed the cause of the stroke. The lack of direct evidence linking many sources of cardioembolism to stroke emphasizes the need for a thorough investigation of all possible causes of stroke.

 

DIAGNOSTIC EVALUATION

2. Which is the best study to evaluate for a cardiac embolic source in this patient?

• Transthoracic echocardiography (TTE)
• Transesophageal echocardiography (TEE)
• Transcranial Doppler ultrasonography
• Electrocardiography

The study of choice in this patient is TEE. Overall, TEE is better than TTE in identifying a cardiac source of embolism,^18,19 mainly because the images are obtained from a probe in the esophagus, which is in close proximity to the heart, so that there is little additional soft tissue and bone between the probe and cardiac structures. In addition, higher-frequency probes can be used. Both of these result in ultrasonographic images with much greater spatial resolution than can be obtained with a transthoracic study.¹⁵

In a case series,²⁰ TEE identified a potential cardiac source of embolism in 45 (57%) of 79 patients with cryptogenic stroke, compared with only 12 (15%) with TTE.

The main limitation of TEE is that it does not show the left ventricular apex very well, making an accurate assessment of left ventricular function or identification of a left ventricular apical thrombus much less likely.

In patients who lack evidence of atherosclerotic cerebrovascular disease, specific findings on history or physical examination could increase the chances of identifying an embolic source, such as left ventricular thrombus, on TTE. These findings could include a history of a myocardial infarction, congestive heart failure, left ventricular dysfunction, endocarditis, rheumatic heart disease, a prosthetic valve, or atrial fibrillation or flutter. TTE by itself is considered sufficient for making the diagnosis of mitral stenosis, left ventricular aneurysm, dilated cardiomyopathy, left ventricular thrombus, and mitral valve prolapse with myxomatous degeneration of the leaflets.

However, in patients without signs or symptoms of cardiac disease, the diagnostic value of TTE is significantly less. Several studies have demonstrated that in patients without evidence of cardiac disease, TTE identifies the source of embolism less than 10% of the time.²¹ Some series even suggest that the yield may be less than 1%.²² TEE has the advantage of being able to diagnose the above disorders and of having a higher sensitivity for identifying potential sources that may be missed by TTE, such as left atrial or left atrial appendage thrombus, aortic arch atheroma, patent foramen ovale, atrial septal aneurysm, or spontaneous echo contrast. It should be remembered, however, that TEE is a semi-invasive procedure that carries the risks of both the procedure and the sedation, eg, bronchospasm, hypoxia, arrhythmias, upper gastrointestinal trauma, and bleeding.²³

Further clouding the decision are recent advances in TTE technology, such as contrast TTE with second harmonic imaging, which enhances the ability of TTE to identify potential sources of stroke such as patent foramen ovale nearly to the level of TEE.²⁴

Unfortunately, guidelines from professional societies do not offer assistance on the best diagnostic approach. Current guidelines from the American Heart Association, American College of Cardiology, and American Society of Echocardiography do give echocardiography a class I indication in younger patients (< 45 years old) with cerebrovascular events or older patients (> 45 years old) with stroke without evidence of cerebrovascular disease or other obvious causes. However, there is no official recommendation on whether to choose TTE, TEE, or both studies.¹⁶ Given the multiple causes of cardioembolism and the variety of clinical factors that could influence the decision to choose a certain echo study, this decision is appropriately left to the individual physician.

A reasonable, evidence-based diagnostic approach in young stroke patients is to proceed to TEE when routine TTE and electrocardiography are unrevealing.²⁵ In reality, this is the practice followed in most centers, including ours. Although TTE has a lower diagnostic yield in patients without symptoms, it has the advantages of being readily available in most centers, being noninvasive, and providing complementary information to TEE even when TTE does not reveal a potential cause of stroke.

As for the other studies:

Electrocardiography is valuable in identifying potential cardioembolic causes of stroke such as atrial fibrillation, left ventricular aneurysm, or myocardial infarction, but it is insufficient by itself to assess for many other potential sources of cardioembolism.

Transcranial Doppler ultrasonography is very sensitive for detecting patent foramen ovale and other right-to-left shunts that could be sources of cardioembolism. In this test, microbubbles from agitated saline are injected into the venous circulation and are detected in the cerebral arteries after passing through the shunt. It has no utility in identifying the other possibilities discussed above, nor can it discriminate whether these shunts are intra-cardiac or extracardiac.

Case continued

The patient undergoes TTE, which shows normal left ventricular size, wall thickness, and systolic function. His right ventricular function is normal, as are his left and right atrial size. Valvular function is normal, and no right-to-left interatrial shunt is detected with the use of agitated saline contrast.

The patient then undergoes TEE, which reveals a 9- by 8-mm mobile soft-tissue mass attached to the aortic side of the aortic valve at the junction of the right and left coronary cusps (Figure 3). There is trivial aortic insufficiency, and the rest of the aorta appears normal. This lesion is consistent with a valvular papillary fibroelastoma.

 

MANAGEMENT

3. Which is the most appropriate way to manage the lesion?

• Surgical resection
• Periodic echocardiographic follow-up
• Anticoagulation and periodic echocardiographic follow-up

Cardiac papillary fibroelastomas are rare benign primary tumors of the heart. The true incidence is unknown because, when small, they can be asymptomatic and easily overlooked on gross examination. In adults, they are the second most common primary cardiac tumors, next to atrial myxoma.²⁶

These tumors primarily affect the valves (most often the aortic valve), and consist of a small, highly papillary, avascular tumor covered by a single layer of endothelium, containing variable amounts of fine elastic fibers arranged around a central hyaline stroma (Figure 4).²⁷ Most of the tumors are sessile, while a few are attached to the valve by a short stalk.

The histogenesis is not known, but the mean age at which they are detected is approximately 60 years, and most of the patients are men, likely because most of these tumors are found incidentally during echocardiography, open heart surgery, or autopsy.²⁸

Most patients with cardiac papillary fibroelastomas have no symptoms; however, those who do have symptoms usually experience valve obstruction or embolization of tumor fragments, leading to stroke, myocardial infarction, or sudden death. Further increasing the risk of embolism, thrombus has been reported on the surface of some tumors, supporting the use of anticoagulation in patients who have experienced embolic phenomena.²⁹

A case review of 725 patients with these tumors²⁷ found that tumor mobility and location on the aortic valve were univariate predictors of tumor-related death and of nonfatal embolism. The only independent predictor of tumor-related death or nonfatal embolization was tumor mobility.

Surgical resection of the tumor is curative, and no recurrences have been reported, although the longest follow-up period has been 11 years.

Although no data exist to support the practice, patients with nonmobile or nonaortic valve tumors could be managed with anticoagulation and periodic echocardiographic follow-up until the tumor becomes mobile or symptomatic, but such a conservative strategy would seem inappropriate for our patient. His tumor is both mobile and located on the aortic valve, putting him at risk of death, and he has already experienced an embolic complication. Therefore, his lesion should be surgically resected.

Case continued

The patient receives anticoagulation therapy with subcutaneous enoxaparin (Lovenox) and warfarin (Coumadin). He undergoes successful surgical resection of the tumor without complication and is discharged to home on hospital day 5.

TAKE-HOME POINTS

The potential causes of stroke in patients younger than age 45 differ significantly from those in older patients. Cardiac embolism is the most frequent cause of stroke in young patients and is most often from left atrial or ventricular thrombus or from aortic atheroma.

In young patients, TEE is superior to TTE in identifying a specific source of cardiac embolism, particularly when clues from the history or physical examination are lacking and the preliminary diagnostic workup fails to identify the cause of the stroke.

Our patient’s history, physical examination, MRI, MRA, electrocardiography, and TTE all failed to disclose a probable cause of his stroke. Appropriately, TEE was performed, which confirmed the diagnosis of cardiac papillary fibroelastoma, a rare and benign primary tumor of the heart with the potential for disastrous consequences.