Clinical Care Conundrums

A 29‐year‐old man developed palpitations and dyspnea while loading boxes into a truck. In the emergency department, telemetry demonstrated a wide‐complex tachycardia at a rate of 204 beats per minute. The patient spontaneously cardioverted to sinus rhythm (Figure 1) before direct current cardioversion was performed.

Figure 1

Wide‐complex tachycardia is usually explained by a supraventricular tachycardia with aberrant ventricular conduction or a ventricular tachycardia. Although algorithms exist to guide the clinician in parsing out those etiologies, often the knowledge of underlying structural cardiac disease is most informative. In patients with a history of myocardial infarction, greater than 95% of wide‐complex tachycardia is ventricular tachycardia. The ventricular ectopy, T‐wave inversion or flattening, and poor R‐wave progression are suggestive of a cardiomyopathy, either acute or chronic. A pressing concern, especially with the Q waves and concave ST morphology in V1 and V2, would be coronary ischemia. His age makes this less likely, but an aberrant coronary circulation or drug use could account for it.

Over the past 2 years, the patient had several episodes of sustained palpitations, which terminated after several minutes. Previously, the patient exercised frequently including playing rugby in college. However, over the past year he experienced difficulty climbing stairs due to shortness of breath, which he attributed to deconditioning and smoking. He had no significant medical history, was not taking any medications, nor did he use recreational stimulants. He drank alcohol occasionally. He had no risk factors for the human immunodeficiency virus (HIV). Both of the patient's parents were alive and well. There was no family history of sudden cardiac death.

The duration of symptoms suggests that this is a chronic cardiomyopathy rather than acute myocarditis or acute ischemia, acknowledging that either one could be superimposed. The absence of family history lowers the likelihood of heritable causes of arrhythmia that may accompany a structurally normal (eg, long QT syndrome) or abnormal (eg, hypertrophic cardiomyopathy) heart, although penetrance can be variable. What might account for a cardiomyopathy in a young person? Most cases are probably idiopathic, but etiologies that diverge from the usual suspects of coronary artery disease, hypertension, and valvular disease, which affect an older population, include antecedent viral myocarditis, substance abuse, HIV, or infiltrative disorders such as sarcoidosis.

The patient's pulse was 92 beats per minute and regular and the blood pressure was 96/52 mm Hg. The jugular venous pressure was elevated with prominent v‐waves, the point of maximal impulse was diffuse, there were no extra heart sounds or murmurs, and an enlarged liver was detected. An echocardiogram demonstrated left ventricular dysfunction with an ejection fraction of 30%, severe enlargement of the right atrium and right ventricle, and moderate tricuspid regurgitation. Cardiac catheterization revealed normal coronary arteries without evidence of pulmonary hypertension or intracardiac shunt.

The physical examination and echocardiographic findings of right‐sided failure are unusual given the absence of pulmonary hypertension or intracardiac shunt, and could prompt repeat of the hemodynamic measurements and/or investigations for pulmonary disease that may account for right‐sided pressure overload (in addition to that caused by left ventricular failure). An alternative explanation would be a cardiomyopathic process that preferentially involves the right side of the heart, such as arrhythmogenic right ventricular dysplasia (ARVD), but that would not satisfactorily explain the significant decline in left ventricular function. An acute right ventricular infarction could cause his acute symptoms and his examination and echocardiographic findings, but not the underlying chronic illness. It is common to see patients with long‐standing biventricular failure who present with prominent signs of right‐sided failure (elevated neck veins, hepatomegaly, and edema) but limited or no signs of left‐sided failure (rales) to match their degree of volume overload or dyspnea.

Cardiac magnetic resonance imaging (MRI) revealed a dilated right ventricle with extensive hyperenhancement, a right ventricular ejection fraction of 9%, and moderate left ventricular dysfunction (Figure 2). Electrophysiology testing induced both nonsustained polymorphic and monomorphic ventricular tachycardia. Late potentials were detected on a signal‐averaged electrocardiogram. A single‐chamber cardioverter defibrillator was implanted and the patient was discharged on carvedilol, lisinopril, and spironolactone. An HIV‐1 antibody was negative and a thyroid‐stimulating hormone concentration was within normal limits.

Figure 2

Assuming that accurate evaluation of the pulmonary circulation has been undertaken to exclude pulmonary hypertension, the enlarged and hyperenhanced right ventricle on MRI suggests a process that preferentially infiltrates the right ventricular myocardium, and may secondarily affect the left ventricle either by further infiltration or as a consequence of altered mechanics from the highly dysfunctional right ventricle. ARVD affects the right ventricle, but it is possible that another infiltrative cardiomyopathy, such as sarcoid or an antecedent viral infection, could be restricted in its distribution. Late‐potentials identified on signal average electrocardiograms indicate areas of abnormal conduction that may serve as substrate for reentrant ventricular arrhythmias. They are, however, nonspecific, as they are seen in a variety of myocardial diseases.

The patient continued to have progressive dyspnea and was readmitted after receiving an appropriate implantable cardioverter defibrillator shock for ventricular tachycardia. Recurrent slow ventricular tachycardia (Figure 3) was treated with supplemental beta‐blockade and amiodarone (10 g total). Repeat echocardiography demonstrated severe left ventricular dysfunction with an ejection fraction of less than 15%. There were no recurrences of ventricular arrhythmias and the patient was discharged and referred for cardiac transplant evaluation for ARVD.

Figure 3

This degree of left ventricular dysfunction is unlikely to be accounted for by altered mechanics and interactions from a failing right ventricle alone and frames this as a biventricular cardiomyopathy, which has an extensive differential diagnosis and requires information from the general medical evaluation.

On routine laboratory testing 6 months later, a serum aspartate aminotransferase of 79 units/L and a serum alanine aminotransferase of 118 units/L were found. Bilirubin, albumin, and alkaline phosphatase were normal. The transaminase levels had been normal on initial evaluation. The patient reported that 2 paternal uncles had end‐stage nonalcoholic cirrhosis. Transjugular liver biopsy was consistent with mild lobular hepatitis with mild portal fibrosis with a few lobular collections of mononuclear cells. There was no evidence of iron overload. The hepatic venogram and transhepatic pressure gradient (2 mm Hg) were normal.

The elevated transaminase levels could be due to amiodarone‐associated hepatotoxicity, hepatic congestion, or a primary liver disease. It is important to consider combined cardiohepatic syndromes such as hemochromatosis, sarcoidosis, or amyloidosis. The relatively normal liver histology and normal hepatic hemodynamics do not suggest a significant primary intrinsic liver disease. The 2 uncles with cirrhosis could suggest a heritable liver disease, although cirrhosis in multiple family members is frequently accounted for by shared habits such as alcohol consumption or excessive caloric intake. Liver disorders with a genetic component, such as hemochromatosis, Wilson's disease, and alpha‐1‐antitrypsin deficiency are mostly autosomal recessive, which would make this pattern of transmission unusual. Furthermore, aside from hemochromatosis, these genetic hepatic disorders have few cardiac manifestations. Right‐sided congestion and amiodarone appear to be the most likely explanations of his liver abnormalities.

Pulmonary function testing revealed normal lung volumes without obstruction, but the diffusing capacity for carbon monoxide was substantially reduced. Computed tomography of the chest identified scattered ground‐glass opacities as well as small nodules with an upper lobe distribution (Figure 4). Although not reported on the initial interpretation, review of a chest x‐ray taken 6 months previously also demonstrated small nodules in the upper lobe distribution. Bronchoscopic examination was normal. Bronchioalveolar lavage fluid stains and cultures for bacteria, mycobacteria, Pneumocystis, and fungus were negative. Transbronchial biopsies of the right middle lobe had no evidence of infection, malignancy, or granulomatous inflammation. The patient continued to have progressive New York Heart Association Class IV heart failure symptoms. Repeat right heart catheterization was notable for a cardiac index of 1.4 L/minute/m². The mean pulmonary artery pressure was 20 mm Hg. An intraaortic balloon pump was placed for refractory cardiogenic shock.

Figure 4

The reduced diffusion capacity and ground‐glass opacities suggest an interstitial process, which may have been missed on transbronchial biopsy because of sampling error. His pulmonary disease is likely another manifestation of his infiltrative cardiac disease. The constellation of cardiac, pulmonary, and hepatic involvement in the context of progressive dyspnea over 2 years is suggestive of sarcoidosis although the absence of hilar lymphadenopathy and 2 biopsy specimens without granulomas argue against the diagnosis, and the effects of amiodarone on the latter 2 organs cannot be ignored. On the limited menu of pharmacologic treatments that may treat this severe and progressive cardiomyopathy are steroids, which makes a diligent search for a steroid‐responsive syndrome important. Therefore, despite the negative studies, sarcoidosis must be investigated to the fullest extent with either an endomyocardial biopsy or surgical lung biopsy.

The patient underwent cardiac transplantation. The native heart was found to have right ventricular thinning, which was most notable at the right ventricular outflow tract. Microscopic examination revealed extensive fibrosis and granulomatous inflammation (Figure 5) with scarring typical of cardiac sarcoidosis. Six months after cardiac transplantation, the patient is doing well on prednisone, tacrolimus, and mycophenolate mofetil. Follow‐up chest x‐rays show resolution of the pulmonary nodules.

Figure 5

COMMENTARY

Cardiomyopathy in a young person is a relatively uncommon clinical event that prompts consideration of a broad differential diagnosis that is notably different from the most common etiologies of cardiomyopathy in older adults. This case highlights the challenges of arriving at a diagnosis in the absence of a gold standard, and the greater challenges of modifying initial diagnostic impressions as new clinical data become available.

After encountering ventricular tachycardia and right ventricular dysfunction in a young patient, the clinicians arrived at the diagnosis of ARVD. This rare and progressive disorder is associated with up to 20% of ventricular arrhythmias and sudden death in the young,1, 2 but can be challenging to diagnose. Despite common referrals for cardiac MRI to exclude ARVD, cardiac MRI is not the gold standard for diagnosis and is the most common method of misdiagnosis of ARVD.3 A diagnosis of ARVD requires the presence of 2 major, 1 major and 2 minor, or 4 minor International Task Force criteria (Table 1).4, 5 While the diagnostic criteria provide standardization across populations (eg, in clinical studies), additional considerations are needed in the management of individual patients. Scoring systems serve as a tool, but the final diagnosis requires balancing such criteria with competing hypotheses. This dilemma is familiar to clinicians considering other less common conditions such as amyotrophic lateral sclerosis (World Neurology Foundation), rheumatic fever (Jones criteria), or systemic lupus erythematosus (American College of Rheumatology). This patient's cardiac MRI findings, precordial T‐wave inversions, frequent ventricular ectopy, and late potentials on a signal‐averaged electrocardiogram fulfilled the International Task Force criteria for a diagnosis of ARVD. Discordant information included the right bundle branch pattern of the ventricular tachycardia, which suggested left ventricular origin, as opposed to the more common left bundle branch pattern observed in ARVD, and the absence of a family history. In addition, in U.S. populations only 25% of cases present with heart failure and fewer than 5% develop biventricular failure.6 Nonetheless, this patient's imaging evidence of right ventricular structural abnormalities and dysfunction and electrocardiographic abnormalities coupled with the absence of obvious systemic disease made ARVD the logical working diagnosis.

When more widespread manifestations developed, namely hepatic and pulmonary abnormalities, each was investigated with imaging and biopsy. Once a multisystem illness became apparent, the discussant reframed the patient's illness to include other diagnostic possibilities. In practice it is difficult to reverse a working diagnosis despite contradictory evidence because of the common pitfall of anchoring bias. Tversky and Kahneman7 were the first to describe the cognitive processes behind probability assessment and decision making in time‐sensitive situations. Under these conditions, decision makers tend to focus on the first symptom, striking feature, or diagnosis and anchor subsequent probabilities to that initial presentation. Once a decision or diagnosis has been reached, clinicians tend to interpret subsequent findings in the context of the original diagnosis rather than reevaluating their initial impression. In the setting of a known diagnosis of ARVD, 3 separate diagnoses (ARVD, amiodarone‐associated lung injury, and amiodarone‐induced hepatic dysfunction) were considered by the treating physicians. The initial diagnosis of ARVD followed by the sequential rather than simultaneous manifestations of sarcoidosis made arriving at the revised diagnosis even more challenging.

Cardiac sarcoidosis is a mimic of ARVD and should be considered when evaluating a patient for right ventricular dysplasia.8, 9 The differential diagnosis of ARVD includes idiopathic ventricular tachycardia, myocarditis, idiopathic cardiomyopathy, and sarcoidosis. Cardiac sarcoidosis can present as ventricular ectopy, sustained ventricular arrhythmias, asymptomatic ventricular dysfunction, heart failure, or sudden death.10 Although 25% of patients with sarcoidosis have evidence of cardiac involvement at autopsy, only 5% have clinical manifestations.11 Those patients with clinical evidence of cardiac sarcoidosis have a wide range of clinical findings (Table 2). While the patient's cardiomyopathy was advanced, it is possible that earlier administration of corticosteroid therapy may have arrested his progressive biventricular failure. As clinicians, we should always remember to force ourselves to broaden our differential diagnosis when new findings become available, especially those that point to a systemicrather than an organ‐specificdisorder. In this case, while the original diagnostic findings were accurate and strongly suggested ARVD, a change of heart was needed to arrive at the ultimate diagnosis.

KEY POINTS FOR HOSPITALISTS

• 1

  Cardiomyopathy in a young person requires consideration of a broad differential diagnosis that is notably different from the most common etiologies of cardiomyopathy in the elderly.

• 2

  Anchoring bias is a common pitfall in clinical decision making. When new or contradictory findings are uncovered, clinicians should reevaluate their initial impression to ensure it remains the most likely diagnosis.

• 3

  Cardiac sarcoidosis is a mimic of ARVD and should be considered when evaluating a patient for right ventricular cardiomyopathy. The differential diagnosis of ARVD includes idiopathic ventricular tachycardia, right ventricular outflow tract tachycardia, myocarditis, idiopathic dilated cardiomyopathy, and sarcoidosis.

A 29‐year‐old man developed palpitations and dyspnea while loading boxes into a truck. In the emergency department, telemetry demonstrated a wide‐complex tachycardia at a rate of 204 beats per minute. The patient spontaneously cardioverted to sinus rhythm (Figure 1) before direct current cardioversion was performed.

Figure 1

Wide‐complex tachycardia is usually explained by a supraventricular tachycardia with aberrant ventricular conduction or a ventricular tachycardia. Although algorithms exist to guide the clinician in parsing out those etiologies, often the knowledge of underlying structural cardiac disease is most informative. In patients with a history of myocardial infarction, greater than 95% of wide‐complex tachycardia is ventricular tachycardia. The ventricular ectopy, T‐wave inversion or flattening, and poor R‐wave progression are suggestive of a cardiomyopathy, either acute or chronic. A pressing concern, especially with the Q waves and concave ST morphology in V1 and V2, would be coronary ischemia. His age makes this less likely, but an aberrant coronary circulation or drug use could account for it.

Over the past 2 years, the patient had several episodes of sustained palpitations, which terminated after several minutes. Previously, the patient exercised frequently including playing rugby in college. However, over the past year he experienced difficulty climbing stairs due to shortness of breath, which he attributed to deconditioning and smoking. He had no significant medical history, was not taking any medications, nor did he use recreational stimulants. He drank alcohol occasionally. He had no risk factors for the human immunodeficiency virus (HIV). Both of the patient's parents were alive and well. There was no family history of sudden cardiac death.

The duration of symptoms suggests that this is a chronic cardiomyopathy rather than acute myocarditis or acute ischemia, acknowledging that either one could be superimposed. The absence of family history lowers the likelihood of heritable causes of arrhythmia that may accompany a structurally normal (eg, long QT syndrome) or abnormal (eg, hypertrophic cardiomyopathy) heart, although penetrance can be variable. What might account for a cardiomyopathy in a young person? Most cases are probably idiopathic, but etiologies that diverge from the usual suspects of coronary artery disease, hypertension, and valvular disease, which affect an older population, include antecedent viral myocarditis, substance abuse, HIV, or infiltrative disorders such as sarcoidosis.

The patient's pulse was 92 beats per minute and regular and the blood pressure was 96/52 mm Hg. The jugular venous pressure was elevated with prominent v‐waves, the point of maximal impulse was diffuse, there were no extra heart sounds or murmurs, and an enlarged liver was detected. An echocardiogram demonstrated left ventricular dysfunction with an ejection fraction of 30%, severe enlargement of the right atrium and right ventricle, and moderate tricuspid regurgitation. Cardiac catheterization revealed normal coronary arteries without evidence of pulmonary hypertension or intracardiac shunt.

The physical examination and echocardiographic findings of right‐sided failure are unusual given the absence of pulmonary hypertension or intracardiac shunt, and could prompt repeat of the hemodynamic measurements and/or investigations for pulmonary disease that may account for right‐sided pressure overload (in addition to that caused by left ventricular failure). An alternative explanation would be a cardiomyopathic process that preferentially involves the right side of the heart, such as arrhythmogenic right ventricular dysplasia (ARVD), but that would not satisfactorily explain the significant decline in left ventricular function. An acute right ventricular infarction could cause his acute symptoms and his examination and echocardiographic findings, but not the underlying chronic illness. It is common to see patients with long‐standing biventricular failure who present with prominent signs of right‐sided failure (elevated neck veins, hepatomegaly, and edema) but limited or no signs of left‐sided failure (rales) to match their degree of volume overload or dyspnea.

Cardiac magnetic resonance imaging (MRI) revealed a dilated right ventricle with extensive hyperenhancement, a right ventricular ejection fraction of 9%, and moderate left ventricular dysfunction (Figure 2). Electrophysiology testing induced both nonsustained polymorphic and monomorphic ventricular tachycardia. Late potentials were detected on a signal‐averaged electrocardiogram. A single‐chamber cardioverter defibrillator was implanted and the patient was discharged on carvedilol, lisinopril, and spironolactone. An HIV‐1 antibody was negative and a thyroid‐stimulating hormone concentration was within normal limits.

Figure 2

Assuming that accurate evaluation of the pulmonary circulation has been undertaken to exclude pulmonary hypertension, the enlarged and hyperenhanced right ventricle on MRI suggests a process that preferentially infiltrates the right ventricular myocardium, and may secondarily affect the left ventricle either by further infiltration or as a consequence of altered mechanics from the highly dysfunctional right ventricle. ARVD affects the right ventricle, but it is possible that another infiltrative cardiomyopathy, such as sarcoid or an antecedent viral infection, could be restricted in its distribution. Late‐potentials identified on signal average electrocardiograms indicate areas of abnormal conduction that may serve as substrate for reentrant ventricular arrhythmias. They are, however, nonspecific, as they are seen in a variety of myocardial diseases.

The patient continued to have progressive dyspnea and was readmitted after receiving an appropriate implantable cardioverter defibrillator shock for ventricular tachycardia. Recurrent slow ventricular tachycardia (Figure 3) was treated with supplemental beta‐blockade and amiodarone (10 g total). Repeat echocardiography demonstrated severe left ventricular dysfunction with an ejection fraction of less than 15%. There were no recurrences of ventricular arrhythmias and the patient was discharged and referred for cardiac transplant evaluation for ARVD.

Figure 3

This degree of left ventricular dysfunction is unlikely to be accounted for by altered mechanics and interactions from a failing right ventricle alone and frames this as a biventricular cardiomyopathy, which has an extensive differential diagnosis and requires information from the general medical evaluation.

On routine laboratory testing 6 months later, a serum aspartate aminotransferase of 79 units/L and a serum alanine aminotransferase of 118 units/L were found. Bilirubin, albumin, and alkaline phosphatase were normal. The transaminase levels had been normal on initial evaluation. The patient reported that 2 paternal uncles had end‐stage nonalcoholic cirrhosis. Transjugular liver biopsy was consistent with mild lobular hepatitis with mild portal fibrosis with a few lobular collections of mononuclear cells. There was no evidence of iron overload. The hepatic venogram and transhepatic pressure gradient (2 mm Hg) were normal.

The elevated transaminase levels could be due to amiodarone‐associated hepatotoxicity, hepatic congestion, or a primary liver disease. It is important to consider combined cardiohepatic syndromes such as hemochromatosis, sarcoidosis, or amyloidosis. The relatively normal liver histology and normal hepatic hemodynamics do not suggest a significant primary intrinsic liver disease. The 2 uncles with cirrhosis could suggest a heritable liver disease, although cirrhosis in multiple family members is frequently accounted for by shared habits such as alcohol consumption or excessive caloric intake. Liver disorders with a genetic component, such as hemochromatosis, Wilson's disease, and alpha‐1‐antitrypsin deficiency are mostly autosomal recessive, which would make this pattern of transmission unusual. Furthermore, aside from hemochromatosis, these genetic hepatic disorders have few cardiac manifestations. Right‐sided congestion and amiodarone appear to be the most likely explanations of his liver abnormalities.

Pulmonary function testing revealed normal lung volumes without obstruction, but the diffusing capacity for carbon monoxide was substantially reduced. Computed tomography of the chest identified scattered ground‐glass opacities as well as small nodules with an upper lobe distribution (Figure 4). Although not reported on the initial interpretation, review of a chest x‐ray taken 6 months previously also demonstrated small nodules in the upper lobe distribution. Bronchoscopic examination was normal. Bronchioalveolar lavage fluid stains and cultures for bacteria, mycobacteria, Pneumocystis, and fungus were negative. Transbronchial biopsies of the right middle lobe had no evidence of infection, malignancy, or granulomatous inflammation. The patient continued to have progressive New York Heart Association Class IV heart failure symptoms. Repeat right heart catheterization was notable for a cardiac index of 1.4 L/minute/m². The mean pulmonary artery pressure was 20 mm Hg. An intraaortic balloon pump was placed for refractory cardiogenic shock.

Figure 4

The reduced diffusion capacity and ground‐glass opacities suggest an interstitial process, which may have been missed on transbronchial biopsy because of sampling error. His pulmonary disease is likely another manifestation of his infiltrative cardiac disease. The constellation of cardiac, pulmonary, and hepatic involvement in the context of progressive dyspnea over 2 years is suggestive of sarcoidosis although the absence of hilar lymphadenopathy and 2 biopsy specimens without granulomas argue against the diagnosis, and the effects of amiodarone on the latter 2 organs cannot be ignored. On the limited menu of pharmacologic treatments that may treat this severe and progressive cardiomyopathy are steroids, which makes a diligent search for a steroid‐responsive syndrome important. Therefore, despite the negative studies, sarcoidosis must be investigated to the fullest extent with either an endomyocardial biopsy or surgical lung biopsy.

The patient underwent cardiac transplantation. The native heart was found to have right ventricular thinning, which was most notable at the right ventricular outflow tract. Microscopic examination revealed extensive fibrosis and granulomatous inflammation (Figure 5) with scarring typical of cardiac sarcoidosis. Six months after cardiac transplantation, the patient is doing well on prednisone, tacrolimus, and mycophenolate mofetil. Follow‐up chest x‐rays show resolution of the pulmonary nodules.

Figure 5

COMMENTARY

Cardiomyopathy in a young person is a relatively uncommon clinical event that prompts consideration of a broad differential diagnosis that is notably different from the most common etiologies of cardiomyopathy in older adults. This case highlights the challenges of arriving at a diagnosis in the absence of a gold standard, and the greater challenges of modifying initial diagnostic impressions as new clinical data become available.

After encountering ventricular tachycardia and right ventricular dysfunction in a young patient, the clinicians arrived at the diagnosis of ARVD. This rare and progressive disorder is associated with up to 20% of ventricular arrhythmias and sudden death in the young,1, 2 but can be challenging to diagnose. Despite common referrals for cardiac MRI to exclude ARVD, cardiac MRI is not the gold standard for diagnosis and is the most common method of misdiagnosis of ARVD.3 A diagnosis of ARVD requires the presence of 2 major, 1 major and 2 minor, or 4 minor International Task Force criteria (Table 1).4, 5 While the diagnostic criteria provide standardization across populations (eg, in clinical studies), additional considerations are needed in the management of individual patients. Scoring systems serve as a tool, but the final diagnosis requires balancing such criteria with competing hypotheses. This dilemma is familiar to clinicians considering other less common conditions such as amyotrophic lateral sclerosis (World Neurology Foundation), rheumatic fever (Jones criteria), or systemic lupus erythematosus (American College of Rheumatology). This patient's cardiac MRI findings, precordial T‐wave inversions, frequent ventricular ectopy, and late potentials on a signal‐averaged electrocardiogram fulfilled the International Task Force criteria for a diagnosis of ARVD. Discordant information included the right bundle branch pattern of the ventricular tachycardia, which suggested left ventricular origin, as opposed to the more common left bundle branch pattern observed in ARVD, and the absence of a family history. In addition, in U.S. populations only 25% of cases present with heart failure and fewer than 5% develop biventricular failure.6 Nonetheless, this patient's imaging evidence of right ventricular structural abnormalities and dysfunction and electrocardiographic abnormalities coupled with the absence of obvious systemic disease made ARVD the logical working diagnosis.

When more widespread manifestations developed, namely hepatic and pulmonary abnormalities, each was investigated with imaging and biopsy. Once a multisystem illness became apparent, the discussant reframed the patient's illness to include other diagnostic possibilities. In practice it is difficult to reverse a working diagnosis despite contradictory evidence because of the common pitfall of anchoring bias. Tversky and Kahneman7 were the first to describe the cognitive processes behind probability assessment and decision making in time‐sensitive situations. Under these conditions, decision makers tend to focus on the first symptom, striking feature, or diagnosis and anchor subsequent probabilities to that initial presentation. Once a decision or diagnosis has been reached, clinicians tend to interpret subsequent findings in the context of the original diagnosis rather than reevaluating their initial impression. In the setting of a known diagnosis of ARVD, 3 separate diagnoses (ARVD, amiodarone‐associated lung injury, and amiodarone‐induced hepatic dysfunction) were considered by the treating physicians. The initial diagnosis of ARVD followed by the sequential rather than simultaneous manifestations of sarcoidosis made arriving at the revised diagnosis even more challenging.

Cardiac sarcoidosis is a mimic of ARVD and should be considered when evaluating a patient for right ventricular dysplasia.8, 9 The differential diagnosis of ARVD includes idiopathic ventricular tachycardia, myocarditis, idiopathic cardiomyopathy, and sarcoidosis. Cardiac sarcoidosis can present as ventricular ectopy, sustained ventricular arrhythmias, asymptomatic ventricular dysfunction, heart failure, or sudden death.10 Although 25% of patients with sarcoidosis have evidence of cardiac involvement at autopsy, only 5% have clinical manifestations.11 Those patients with clinical evidence of cardiac sarcoidosis have a wide range of clinical findings (Table 2). While the patient's cardiomyopathy was advanced, it is possible that earlier administration of corticosteroid therapy may have arrested his progressive biventricular failure. As clinicians, we should always remember to force ourselves to broaden our differential diagnosis when new findings become available, especially those that point to a systemicrather than an organ‐specificdisorder. In this case, while the original diagnostic findings were accurate and strongly suggested ARVD, a change of heart was needed to arrive at the ultimate diagnosis.

KEY POINTS FOR HOSPITALISTS

• 1

  Cardiomyopathy in a young person requires consideration of a broad differential diagnosis that is notably different from the most common etiologies of cardiomyopathy in the elderly.

• 2

  Anchoring bias is a common pitfall in clinical decision making. When new or contradictory findings are uncovered, clinicians should reevaluate their initial impression to ensure it remains the most likely diagnosis.

• 3

  Cardiac sarcoidosis is a mimic of ARVD and should be considered when evaluating a patient for right ventricular cardiomyopathy. The differential diagnosis of ARVD includes idiopathic ventricular tachycardia, right ventricular outflow tract tachycardia, myocarditis, idiopathic dilated cardiomyopathy, and sarcoidosis.

A 29‐year‐old man developed palpitations and dyspnea while loading boxes into a truck. In the emergency department, telemetry demonstrated a wide‐complex tachycardia at a rate of 204 beats per minute. The patient spontaneously cardioverted to sinus rhythm (Figure 1) before direct current cardioversion was performed.

Figure 1

Wide‐complex tachycardia is usually explained by a supraventricular tachycardia with aberrant ventricular conduction or a ventricular tachycardia. Although algorithms exist to guide the clinician in parsing out those etiologies, often the knowledge of underlying structural cardiac disease is most informative. In patients with a history of myocardial infarction, greater than 95% of wide‐complex tachycardia is ventricular tachycardia. The ventricular ectopy, T‐wave inversion or flattening, and poor R‐wave progression are suggestive of a cardiomyopathy, either acute or chronic. A pressing concern, especially with the Q waves and concave ST morphology in V1 and V2, would be coronary ischemia. His age makes this less likely, but an aberrant coronary circulation or drug use could account for it.

Over the past 2 years, the patient had several episodes of sustained palpitations, which terminated after several minutes. Previously, the patient exercised frequently including playing rugby in college. However, over the past year he experienced difficulty climbing stairs due to shortness of breath, which he attributed to deconditioning and smoking. He had no significant medical history, was not taking any medications, nor did he use recreational stimulants. He drank alcohol occasionally. He had no risk factors for the human immunodeficiency virus (HIV). Both of the patient's parents were alive and well. There was no family history of sudden cardiac death.

The duration of symptoms suggests that this is a chronic cardiomyopathy rather than acute myocarditis or acute ischemia, acknowledging that either one could be superimposed. The absence of family history lowers the likelihood of heritable causes of arrhythmia that may accompany a structurally normal (eg, long QT syndrome) or abnormal (eg, hypertrophic cardiomyopathy) heart, although penetrance can be variable. What might account for a cardiomyopathy in a young person? Most cases are probably idiopathic, but etiologies that diverge from the usual suspects of coronary artery disease, hypertension, and valvular disease, which affect an older population, include antecedent viral myocarditis, substance abuse, HIV, or infiltrative disorders such as sarcoidosis.

The patient's pulse was 92 beats per minute and regular and the blood pressure was 96/52 mm Hg. The jugular venous pressure was elevated with prominent v‐waves, the point of maximal impulse was diffuse, there were no extra heart sounds or murmurs, and an enlarged liver was detected. An echocardiogram demonstrated left ventricular dysfunction with an ejection fraction of 30%, severe enlargement of the right atrium and right ventricle, and moderate tricuspid regurgitation. Cardiac catheterization revealed normal coronary arteries without evidence of pulmonary hypertension or intracardiac shunt.

The physical examination and echocardiographic findings of right‐sided failure are unusual given the absence of pulmonary hypertension or intracardiac shunt, and could prompt repeat of the hemodynamic measurements and/or investigations for pulmonary disease that may account for right‐sided pressure overload (in addition to that caused by left ventricular failure). An alternative explanation would be a cardiomyopathic process that preferentially involves the right side of the heart, such as arrhythmogenic right ventricular dysplasia (ARVD), but that would not satisfactorily explain the significant decline in left ventricular function. An acute right ventricular infarction could cause his acute symptoms and his examination and echocardiographic findings, but not the underlying chronic illness. It is common to see patients with long‐standing biventricular failure who present with prominent signs of right‐sided failure (elevated neck veins, hepatomegaly, and edema) but limited or no signs of left‐sided failure (rales) to match their degree of volume overload or dyspnea.

Cardiac magnetic resonance imaging (MRI) revealed a dilated right ventricle with extensive hyperenhancement, a right ventricular ejection fraction of 9%, and moderate left ventricular dysfunction (Figure 2). Electrophysiology testing induced both nonsustained polymorphic and monomorphic ventricular tachycardia. Late potentials were detected on a signal‐averaged electrocardiogram. A single‐chamber cardioverter defibrillator was implanted and the patient was discharged on carvedilol, lisinopril, and spironolactone. An HIV‐1 antibody was negative and a thyroid‐stimulating hormone concentration was within normal limits.

Figure 2

Assuming that accurate evaluation of the pulmonary circulation has been undertaken to exclude pulmonary hypertension, the enlarged and hyperenhanced right ventricle on MRI suggests a process that preferentially infiltrates the right ventricular myocardium, and may secondarily affect the left ventricle either by further infiltration or as a consequence of altered mechanics from the highly dysfunctional right ventricle. ARVD affects the right ventricle, but it is possible that another infiltrative cardiomyopathy, such as sarcoid or an antecedent viral infection, could be restricted in its distribution. Late‐potentials identified on signal average electrocardiograms indicate areas of abnormal conduction that may serve as substrate for reentrant ventricular arrhythmias. They are, however, nonspecific, as they are seen in a variety of myocardial diseases.

The patient continued to have progressive dyspnea and was readmitted after receiving an appropriate implantable cardioverter defibrillator shock for ventricular tachycardia. Recurrent slow ventricular tachycardia (Figure 3) was treated with supplemental beta‐blockade and amiodarone (10 g total). Repeat echocardiography demonstrated severe left ventricular dysfunction with an ejection fraction of less than 15%. There were no recurrences of ventricular arrhythmias and the patient was discharged and referred for cardiac transplant evaluation for ARVD.

Figure 3

This degree of left ventricular dysfunction is unlikely to be accounted for by altered mechanics and interactions from a failing right ventricle alone and frames this as a biventricular cardiomyopathy, which has an extensive differential diagnosis and requires information from the general medical evaluation.

On routine laboratory testing 6 months later, a serum aspartate aminotransferase of 79 units/L and a serum alanine aminotransferase of 118 units/L were found. Bilirubin, albumin, and alkaline phosphatase were normal. The transaminase levels had been normal on initial evaluation. The patient reported that 2 paternal uncles had end‐stage nonalcoholic cirrhosis. Transjugular liver biopsy was consistent with mild lobular hepatitis with mild portal fibrosis with a few lobular collections of mononuclear cells. There was no evidence of iron overload. The hepatic venogram and transhepatic pressure gradient (2 mm Hg) were normal.

The elevated transaminase levels could be due to amiodarone‐associated hepatotoxicity, hepatic congestion, or a primary liver disease. It is important to consider combined cardiohepatic syndromes such as hemochromatosis, sarcoidosis, or amyloidosis. The relatively normal liver histology and normal hepatic hemodynamics do not suggest a significant primary intrinsic liver disease. The 2 uncles with cirrhosis could suggest a heritable liver disease, although cirrhosis in multiple family members is frequently accounted for by shared habits such as alcohol consumption or excessive caloric intake. Liver disorders with a genetic component, such as hemochromatosis, Wilson's disease, and alpha‐1‐antitrypsin deficiency are mostly autosomal recessive, which would make this pattern of transmission unusual. Furthermore, aside from hemochromatosis, these genetic hepatic disorders have few cardiac manifestations. Right‐sided congestion and amiodarone appear to be the most likely explanations of his liver abnormalities.

Pulmonary function testing revealed normal lung volumes without obstruction, but the diffusing capacity for carbon monoxide was substantially reduced. Computed tomography of the chest identified scattered ground‐glass opacities as well as small nodules with an upper lobe distribution (Figure 4). Although not reported on the initial interpretation, review of a chest x‐ray taken 6 months previously also demonstrated small nodules in the upper lobe distribution. Bronchoscopic examination was normal. Bronchioalveolar lavage fluid stains and cultures for bacteria, mycobacteria, Pneumocystis, and fungus were negative. Transbronchial biopsies of the right middle lobe had no evidence of infection, malignancy, or granulomatous inflammation. The patient continued to have progressive New York Heart Association Class IV heart failure symptoms. Repeat right heart catheterization was notable for a cardiac index of 1.4 L/minute/m². The mean pulmonary artery pressure was 20 mm Hg. An intraaortic balloon pump was placed for refractory cardiogenic shock.

Figure 4

The reduced diffusion capacity and ground‐glass opacities suggest an interstitial process, which may have been missed on transbronchial biopsy because of sampling error. His pulmonary disease is likely another manifestation of his infiltrative cardiac disease. The constellation of cardiac, pulmonary, and hepatic involvement in the context of progressive dyspnea over 2 years is suggestive of sarcoidosis although the absence of hilar lymphadenopathy and 2 biopsy specimens without granulomas argue against the diagnosis, and the effects of amiodarone on the latter 2 organs cannot be ignored. On the limited menu of pharmacologic treatments that may treat this severe and progressive cardiomyopathy are steroids, which makes a diligent search for a steroid‐responsive syndrome important. Therefore, despite the negative studies, sarcoidosis must be investigated to the fullest extent with either an endomyocardial biopsy or surgical lung biopsy.

The patient underwent cardiac transplantation. The native heart was found to have right ventricular thinning, which was most notable at the right ventricular outflow tract. Microscopic examination revealed extensive fibrosis and granulomatous inflammation (Figure 5) with scarring typical of cardiac sarcoidosis. Six months after cardiac transplantation, the patient is doing well on prednisone, tacrolimus, and mycophenolate mofetil. Follow‐up chest x‐rays show resolution of the pulmonary nodules.

Figure 5

COMMENTARY

Cardiomyopathy in a young person is a relatively uncommon clinical event that prompts consideration of a broad differential diagnosis that is notably different from the most common etiologies of cardiomyopathy in older adults. This case highlights the challenges of arriving at a diagnosis in the absence of a gold standard, and the greater challenges of modifying initial diagnostic impressions as new clinical data become available.

After encountering ventricular tachycardia and right ventricular dysfunction in a young patient, the clinicians arrived at the diagnosis of ARVD. This rare and progressive disorder is associated with up to 20% of ventricular arrhythmias and sudden death in the young,1, 2 but can be challenging to diagnose. Despite common referrals for cardiac MRI to exclude ARVD, cardiac MRI is not the gold standard for diagnosis and is the most common method of misdiagnosis of ARVD.3 A diagnosis of ARVD requires the presence of 2 major, 1 major and 2 minor, or 4 minor International Task Force criteria (Table 1).4, 5 While the diagnostic criteria provide standardization across populations (eg, in clinical studies), additional considerations are needed in the management of individual patients. Scoring systems serve as a tool, but the final diagnosis requires balancing such criteria with competing hypotheses. This dilemma is familiar to clinicians considering other less common conditions such as amyotrophic lateral sclerosis (World Neurology Foundation), rheumatic fever (Jones criteria), or systemic lupus erythematosus (American College of Rheumatology). This patient's cardiac MRI findings, precordial T‐wave inversions, frequent ventricular ectopy, and late potentials on a signal‐averaged electrocardiogram fulfilled the International Task Force criteria for a diagnosis of ARVD. Discordant information included the right bundle branch pattern of the ventricular tachycardia, which suggested left ventricular origin, as opposed to the more common left bundle branch pattern observed in ARVD, and the absence of a family history. In addition, in U.S. populations only 25% of cases present with heart failure and fewer than 5% develop biventricular failure.6 Nonetheless, this patient's imaging evidence of right ventricular structural abnormalities and dysfunction and electrocardiographic abnormalities coupled with the absence of obvious systemic disease made ARVD the logical working diagnosis.

When more widespread manifestations developed, namely hepatic and pulmonary abnormalities, each was investigated with imaging and biopsy. Once a multisystem illness became apparent, the discussant reframed the patient's illness to include other diagnostic possibilities. In practice it is difficult to reverse a working diagnosis despite contradictory evidence because of the common pitfall of anchoring bias. Tversky and Kahneman7 were the first to describe the cognitive processes behind probability assessment and decision making in time‐sensitive situations. Under these conditions, decision makers tend to focus on the first symptom, striking feature, or diagnosis and anchor subsequent probabilities to that initial presentation. Once a decision or diagnosis has been reached, clinicians tend to interpret subsequent findings in the context of the original diagnosis rather than reevaluating their initial impression. In the setting of a known diagnosis of ARVD, 3 separate diagnoses (ARVD, amiodarone‐associated lung injury, and amiodarone‐induced hepatic dysfunction) were considered by the treating physicians. The initial diagnosis of ARVD followed by the sequential rather than simultaneous manifestations of sarcoidosis made arriving at the revised diagnosis even more challenging.

Cardiac sarcoidosis is a mimic of ARVD and should be considered when evaluating a patient for right ventricular dysplasia.8, 9 The differential diagnosis of ARVD includes idiopathic ventricular tachycardia, myocarditis, idiopathic cardiomyopathy, and sarcoidosis. Cardiac sarcoidosis can present as ventricular ectopy, sustained ventricular arrhythmias, asymptomatic ventricular dysfunction, heart failure, or sudden death.10 Although 25% of patients with sarcoidosis have evidence of cardiac involvement at autopsy, only 5% have clinical manifestations.11 Those patients with clinical evidence of cardiac sarcoidosis have a wide range of clinical findings (Table 2). While the patient's cardiomyopathy was advanced, it is possible that earlier administration of corticosteroid therapy may have arrested his progressive biventricular failure. As clinicians, we should always remember to force ourselves to broaden our differential diagnosis when new findings become available, especially those that point to a systemicrather than an organ‐specificdisorder. In this case, while the original diagnostic findings were accurate and strongly suggested ARVD, a change of heart was needed to arrive at the ultimate diagnosis.

KEY POINTS FOR HOSPITALISTS

• 1

  Cardiomyopathy in a young person requires consideration of a broad differential diagnosis that is notably different from the most common etiologies of cardiomyopathy in the elderly.

• 2

  Anchoring bias is a common pitfall in clinical decision making. When new or contradictory findings are uncovered, clinicians should reevaluate their initial impression to ensure it remains the most likely diagnosis.

• 3

  Cardiac sarcoidosis is a mimic of ARVD and should be considered when evaluating a patient for right ventricular cardiomyopathy. The differential diagnosis of ARVD includes idiopathic ventricular tachycardia, right ventricular outflow tract tachycardia, myocarditis, idiopathic dilated cardiomyopathy, and sarcoidosis.

A 71‐year‐old African‐American woman presented to the emergency department with chest pain, shortness of breath, and cough. She had initially presented to her primary care physician 2 weeks previously complaining of worsening cough and shortness of breath and was told to continue her inhaled albuterol and glucocorticoids and was prescribed a prednisone taper and an unknown course of antibiotics. She noted no improvement in her symptoms despite compliance with this treatment. Three days prior to admission she described the gradual onset of left‐sided pleuritic chest pain with continued cough, associated with yellow sputum and worsening dyspnea. Review of systems was remarkable for generalized weakness and malaise. She denied fever, chills, orthopnea, paroxysmal nocturnal dyspnea, lower extremity edema, diarrhea, nausea, vomiting, or abdominal pain.

Her past medical history included a diagnosis of chronic obstructive pulmonary disease (COPD) but pulmonary function tests 7 years prior to admission showed an forced expiratory volume in the first second (FEV1)/forced vital capacity (FVC) ratio of 81%. She had a 30 pack‐year history of smoking, but quit 35 years ago. The patient also carried a diagnosis of heart failure, but an echocardiogram done 1 year ago demonstrated a left ventricular ejection fraction of 65% to 70% without diastolic dysfunction but mild right ventricular dilation and hypertrophy. Additionally, she had known nonobstructive coronary atherosclerotic heart disease, dyslipidemia, hypertension, morbid obesity, depression, and a documented chronic right hemidiaphragm elevation.

At this point the history suggests that the patient does not have a clear diagnosis of COPD. The lack of definitive spirometry evidence of chronic airway obstruction concerns me; I think that she may have been mistakenly treated with chronic inhaled steroids and doses of antibiotics for an acute exacerbation of chronic lung disease. Additional review of her history gives some indication of advanced lung disease, with her recent echocardiogram showing strain on the right ventricle with right ventricular hypertrophy and dilation, but there is no mention of the presence or severity of pulmonary hypertension. Nonetheless, I would be concerned that she probably has underlying significant cor pulmonale.

The patient now re‐presents with a worsening of her pulmonary symptoms. Her left‐sided pleuritic pain would make me concerned that she had a pulmonary embolus (PE). This morbidly obese patient with new pulmonary symptoms, right ventricular strain on her previous echocardiogram, and a persistent elevated right hemidiaphragm suggests a presentation of another PE.

At this time I cannot rule out other common possibilities such as infectious pneumonia. If she does have pneumonia, I would be concerned she could be harboring a multidrug‐resistant bacterial infection given her recent course of antibiotics in addition to her use of both chronic inhaled and intermittent oral glucocorticoids.

After gathering the rest of her full medical history, I would focus my physical exam on looking for evidence of parenchymal lung disease, signs of pulmonary hypertension, and pneumonia.

Her surgical history includes a previous hysterectomy, cholecystectomy, hernia repair, and left hepatic lobectomy for a benign mass. Her outpatient medications were ibuprofen, bupropion, fluvastatin, atenolol, potassium, aspirin, clopidogrel, albuterol inhaler, fluticasone/salmeterol inhaler, and omeprazole. She reports an allergy to penicillin and to sulfa drugs. Her mother died of an unknown cancer at age 77 years. She denied any international travel and she has always lived in Georgia.

The patient has been retired since 1992, having previously worked for the U.S. Postal Service. She admits to occasional alcohol intake (2 to 3 drinks a month). No recent travel, surgery, or prolonged immobilization was noted.

On initial examination she was alert and mentally appropriate, but appeared to be in mild respiratory distress with a respiratory rate of 28 breaths/minute. Her blood pressure (BP) was 99/70, heart rate 102, temperature of 38.2C, and oxygen saturation of 93% on room air and 97% on 2 L of oxygen via nasal cannula. Auscultation of her lungs revealed crackles over her left anterior lung field, bronchial breath sounds in the left posterior midlung, and bibasilar crackles. No wheezing was noted. Her cardiovascular exam and the remainder of her physical exam were unremarkable except for morbid obesity.

While my initial thoughts were leaning toward an exacerbation of chronic lung disease or possibly a new PE, at this moment, infection seems more likely. Indeed, her pulmonary findings suggest a left‐sided inflammatory process, and her vital signs meet criteria for systemic inflammatory response syndrome (SIRS). My primary concern is sepsis due to a drug‐resistant bacterial infection, including Staphylococcus aureus or gram‐negative bacteria or possibly more unusual organisms such as Nocardia or fungi, due to her recent use of antibiotics and chronic inhaled steroid use and recent course of oral glucocorticoids.

Conversely, the SIRS could be a manifestation of a noninfectious lung process such as acute interstitial pneumonia or an eosinophilic pneumonia. Given the diagnostic complexity, I would strongly consider consulting a pulmonologist if the patient did not improve quickly. At this point, I would like to review a posterior‐anterior (PA) and lateral chest radiograph, and room air arterial blood gas (ABG) in addition to basic laboratory test values.

Laboratory data obtained on admission was remarkable for a white blood cell (WBC) count of 26,500/L with 75% neutrophils and 6% eosinophils. Hemoglobin was 14.4 gm/dL. Platelet count was 454,000/L. Serum chemistries showed a sodium of 137 mEq/dL, potassium 4.3 mEq/dL, Cl 108 mEq/dL, bicarbonate 19 mEq/dL, blood urea nitrogen (BUN) 8 mg/dL, creatinine 1.0 mg/dL, and glucose 137 mg/dL. Cardiac enzymes were normal. Calcium was 9.8 mg/dL, albumin 2.7 gm/dL, total protein 6.9 gm/dL, AST 36 U/L, ALT 54 U/L and the bilirubin was normal. Chest radiograph (Figure 1) demonstrated a left perihilar infiltrate with air bronchograms and marked right hemidiaphragm elevation as seen on previous films. Unchanged increased interstitial markings were also present. Her electrocardiogram (ECG) showed normal sinus rhythm, normal axis, and QRS duration with nonspecific diffuse T‐wave abnormalities.

Figure 1

Given her presentation, I am worried about how well she is oxygenating and ventilating. An ABG should be done to assess her status more accurately. An albumin of 2.7 gm/dL indicates that she is fairly sick. I would not hesitate to consider testing the patient for human immunodeficiency virus (HIV) given how this information would dramatically change the differential diagnoses of her pulmonary process.

I am still most concerned about sepsis secondary to pneumonia in this patient with multiple chronic comorbidities, underlying chronic lung disease, receiving chronic inhaled glucocorticoids and a recent course of oral glucocorticoids and antibiotics. While I would initiate hydration I do not see a clear indication for early goal‐directed therapy for severe sepsis. In addition to obtaining an ABG and starting intravenous fluids, I would also draw blood cultures, send sputum for gram stain, culture, and sensitivity, and perform a urinalysis. I would also administer empiric antibiotics as quickly as possible based on a number of pneumonia clinical studies suggesting improved outcomes with early antibiotic administration. Because of her use of antibiotics and both inhaled and oral glucocorticoids, she is at higher risk for potentially multidrug‐resistant bacterial pathogens, including Staphyloccocus aureus and gram‐negative bacteria such as Pseudomonas and Klebsiella (Table 1). Therefore, I would initially cover her broadly for these organisms.

In addition to initial treatment choice, the inpatient triage decision is another important issue, especially at a community hospital where intensive care unit (ICU) resources are rare and often the admission decision is between sending a moderately sick patient to a regular floor bed or the medical ICU. Both the American Thoracic Society and Infectious Diseases Society of America support an ICU triage protocol in their guidelines for the management of community‐acquired pneumonia in adults that utilizes the following 9 minor criteria, of which the presence of at least 3 should support ICU admission: respiratory rate 30 breaths/minute; oxygenation index (pressure of oxygen [PaO₂]/fraction of inspired oxygen [FiO₂] ratio) 250; multilobar infiltrates; confusion/disorientation; uremia (BUN level 20 mg/dL); leukopenia (WBC count <4,000 cells/mm³); thrombocytopenia (platelet count <100,000 cells/mm³); hypothermia (core temperature <36C); and hypotension requiring aggressive fluid. Despite the absence of these criteria in this patient, it is important to note that no triage protocol has been adequately prospectively validated. Retrospective study of the minor criteria has found that the presence of at least 2 of the following 3 clinical criteria to have the highest specificity for predicting cardiopulmonary decompensation and subsequent need for ICU care: (1) initial hypotension (BP <90/60) on presentation with response to initial intravenous fluids to a BP >90/60; (2) oxygenation failure as indicated by PaO₂/FiO₂ ratio less than 250; or (3) the presence of multilobar or bilateral infiltrates on chest radiography.

I also want to comment on the relative elevation of her calcium, especially given the low albumin. This may simply be due to volume depletion, as many older patients have asymptomatic mild primary hyperparathyroidism. However, this elevated calcium may be a clue to the underlying lung process. Granulomatous lung disease due to tuberculosis or fungal infection could yield elevated calcium levels via increases in macrophage production of the active vitamin D metabolite calcitriol. This will need to be followed and a parathormone (PTH) level would be the best first test to request if the calcium level remains elevated. If the PTH level is suppressed, granulomatous disease or malignancy would be the more likely cause.

The patient was admitted with a presumptive diagnosis of community‐acquired pneumonia, was started on ceftriaxone and azithromycin, and given intravenous fluids, oxygen, and continued on inhaled salmeterol/fluticasone. Sputum was ordered for gram stain, culture, and sensitivity, and blood cultures were obtained. Urinalysis showed 1‐5 WBCs/high‐power field. Venous thromboembolism prophylaxis was initiated with subcutaneous heparin 5,000 units 8 hours. Her blood pressure normalized rapidly and during the next few days she stated she was feeling better. Despite continued significant wheezing her oxygen saturation remained at 98% on 2 L of oxygen via nasal cannula and she was less tachypneic. Attempts at obtaining an ABG were unsuccessful, and the patient subsequently refused additional attempts. Over the first few days her WBC count remained elevated above 20,000/L, with worsening bandemia (11%), and fever ranging from 38C to 39C. Sputum analysis was initially unsuccessful and blood cultures remained negative.

I am concerned about the persistent fever and elevated WBC count, and want to emphasize that I might have treated her with broader spectrum antibiotics to cover additional multidrug‐resistant bacterial organisms. I would have initially ordered vancomycin to cover methicillin resistant Staphylococcus aureus (MRSA) plus 2 additional antibiotics that cover multidrug‐resistant gram negative pathogens including Pseudomonas aeruginosa.

On the fifth hospital day, her WBC count dropped to 13,400/L and she defervesced. However, her respiratory status worsened during that same day with increased tachypnea. Of note, no results were reported from the initial sputum cultures and they were reordered and a noncontrast chest computed tomography (CT) was also ordered.

I think at this point, even though she has remained stable hemodynamically and oxygenating easily with supplemental oxygen, the question of whether or not her primary process is infectious or noninfectious lingers. I agree with obtaining a chest CT scan.

I am not surprised that sputum was not evaluated despite the orders. Among hospitalized patients with pneumonia, we frequently find that about a third of the time sputum cannot be obtained, about a third of the time it is obtained but the quality is unsatisfactory, and only a third of the time does the sputum sample meet criteria (less than 5 squamous epithelial cells per high‐power field) for adequate interpretation of the gram‐stain and culture result. Unfortunately, no one has developed a better way to improve this process. Nonetheless, I believe we do not try hard enough to obtain sputum in the first hours of evaluating our patients. I joke with our internal medicine residents that they should carry a sputum cup with them when they evaluate a patient with possible pneumonia. One recent prospective study of the value of sputum gram‐staining in community‐acquired pneumonia has found it to be highly specific for identifying Streptococcus pneumoniae or Haemophilus influenzae pneumonia.

The CT scan (Figure 2) performed on hospital day 6 demonstrated consolidation in the left upper lobe with areas of cavitation. There was also interstitial infiltrate extending into the lingula. Elevation of the right hemidiaphragm with atelectasis in both lung bases was also noted. A small effusion was present on the left and possibly a minimal effusion on the right as well. There was no pericardial effusion and only a few small pretracheal and periaortic lymph nodes were noted.

Figure 2

Given her failure to improve significantly after 6 days of antibiotic treatment, and her recent use of glucocorticoids, I would expand my diagnostic considerations to include other necrotizing bacterial infections, tuberculosis, fungus, and Nocardia.

Given the results of the CT scan she was placed in respiratory isolation to rule out active pulmonary tuberculosis. Though tachypneic, her blood pressure and pulse remained stable. However, her oxygen saturation deteriorated, declining to 92% on 2 L of oxygen via nasal cannula during hospital days 6 and 7. Subsequent successful attempts at collecting sputum yielded rapid growth of yeast (not Cryptococcus spp.). Pulmonary and infectious disease consultations were obtained and vancomycin was added to her regimen. The patient subsequently agreed to undergo diagnostic bronchoscopy.

I agree with obtaining input from expert consultants. I think we too often underutilize consultation in patients that are better but not completely better when we are not entirely sure what is going on. Evidence of noncryptococcus yeast in sputum may sometimes indicate colonization with Candida spp. without any significant clinical consequence. This finding may alternatively suggest the possibility of a true fungal pneumonia caused by 1 of the dimorphic fungi, including Histoplasma capsulatum, Paracoccidioides brasiliensis, Blastomyces dermatitides, or Coccidioides immitis. However, in this case there is not a strong epidemiologic patient history of exposure to any of these types of fungi.

Three sputum smears were negative for acid fast bacilli (AFB). Bronchoscopy revealed grossly abnormal mucosa in the left upper lobe and bronchomalacia, but no obstructive lesions. A transthoracic echocardiogram was ordered to evaluate her degree of pulmonary hypertension.

The 3 sputum specimens that were negative for AFB despite cavitary lung disease have high sensitivity for ruling out pulmonary tuberculosis. In addition, given the absence of any bacterial pathogen isolated from these specimens, I would pursue the possibility of other potential fungal pathogens given the patient's subacute course, history of using inhaled and oral corticosteroids, sputum results, and the presence of a cavitary lesion on her CT scan images.

Cytologic examination of the bronchoalveolar lavage (BAL) sample showed a cell differential of 1% bands, 58% neutrophils, 9% lymphs, and 27% eosinophils. The routine postbronchoscopy chest radiograph showed complete opacification of the left lung. The patient's WBC count rose to 26,000/L but she remained afebrile. Echocardiogram was reported to be of very poor quality due to her obesity. The cardiologist reviewing the echocardiogram called the attending physicians and stated there was possibly something in the left pulmonary artery and aortic dissection could not be ruled out.

The presence of eosinophilia on BAL may be a very important clue as to what lung pathology she has. In fact, eosinophilia in this setting may indicate the possibility of parasitic or fungal infection of the lung, or inflammation of the airway associated to drug toxicity, asthma, or environmental toxin exposure. With this additional information, I am concerned that she may be harboring an atypical infection such as an invasive fungus. The echocardiogram results are unclear to me but will need to be clarified with additional testing.

The interpretation of the transbronchial biopsy specimen was limited but suggested invasive pseudomembranous tracheal bronchitis due to aspergillosis. The routine hematoxylin and eosin stain showed portions of alveolar lung tissue and some collapsed submucosal bronchial glands with relatively normal‐looking lung tissue but along the edge of the spaces were obvious fungal organisms. The Gomori's methenamine silver (GMS) stain suggested the presence of Aspergillus organisms (Figure 3). Fungal cultures were also negative for any of the other dimorphic fungi or for molds.

Figure 3

Despite the negative culture results, the overall clinical picture suggests a necrotizing pneumonia caused by an invasive Aspergillus affecting both the bronchial tree and the lower respiratory tract. Generally, necrotizing pneumonias usually have a slow response to antimicrobial therapy. Given the inherent difficulty in differentiating clearly between invasive and noninvasive disease based on a transbronchial biopsy specimen, initiating antifungal therapy for invasive aspergillosis is appropriate in this patient. This patient's recent use of oral glucocorticoids and chronic use of inhaled glucocorticoids are both potential risk factors that predisposed this patient to develop invasive aspergillosis.

Many times we simply follow treatment guidelines for different categories of pneumonia, and have limited or inadequate clinical information to make more definitive diagnoses. While we need these treatment protocols, physicians must avoid falling into the trap that antibiotics treat all infectious etiologies in the lung and we should make reasonable efforts to pin down the etiology. All of us have been fooled by atypical presentations of tuberculosis, fungus, and noninfectious diseases of the lung. I think it behooves us to be vigilant about alternative diagnoses and consider pursuing additional studies whenever the clinical response to initial treatment does not meet our expectations.

Subsequently, the patient's additional cultures remained negative. The official echocardiogram report was read as questionable PE in the pulmonary artery. A spiral CT angiogram revealed a pulmonary artery embolus in the left upper lobe and she was treated with anticoagulation. Her shortness of breath improved steadily and she was successfully discharged after receiving 9 days of oral voriconazole. Outpatient pulmonary function testing documented the presence of chronic obstructive lung disease. She completed a 5‐month course of voriconazole therapy with significant clinical and radiologic improvement of her pulmonary infiltrate. She also completed a 12‐month treatment with warfarin for the concomitant pulmonary embolism. On follow‐up at 12 months she was doing well.

COMMENTARY

Aspergillosis caused particularly by Aspergillus fumigatus is considered an emerging infectious disease that frequently produces significant morbidity and mortality among immunocompromised patients.1, 2 The most frequently‐affected organs by this fungal pathogen include the lung and the central nervous system. There are 3 pathogenic mechanisms of Aspergillus infection of the lung: colonization, hypersensitivity reaction, and invasive aspergillosis.1

Invasive pulmonary aspergillosis is predominantly seen among individuals with severe degrees of immunosuppression as a result of solid‐organ transplantation, immunosuppressive therapies for autoimmune diseases, systemic glucocorticoids, and chemotherapy for hematologic malignancies. Mortality due to invasive aspergillosis continues to be very high (>58%) despite our improved ability to diagnose this condition and newer therapies to treat immunocompromised individuals.1 Invasive aspergillosis can manifest clinically in multiple ways. These include: (1) an invasive vascular process in which fungal organisms invade blood vessels, causing a rapidly progressive and often fatal illness; (2) necrotizing pseudomembranous tracheal bronchitis; (3) chronic necrotizing aspergillosis; (4) bronchopleural fistula; or (5) empyema.35 In our case, while the pathologic findings were most suggestive of an invasive pseudomembranous tracheal bronchitis, the overall clinical picture was most compatible with a necrotizing pneumonia due to invasive aspergillosis.

In addition to the traditional identified risk factors for invasive pulmonary aspergillosis, a number of reports during the last decade have demonstrated the occurrence of invasive aspergillosis in patients with COPD.14 A systematic review of the literature demonstrated that among 1,941 patients with invasive aspergillosis, 26 (1.3%) had evidence of COPD as the main risk factor for developing invasive aspergillosis.1 A single report has associated the potential use of inhaled steroids with the occurrence of invasive aspergillosis in this patient population.2 However, other factors that may promote increased susceptibility to invasive fungal infection among patients with COPD include the use of long‐term or repeated short‐term glucocorticoid treatments, and the presence of multiple additional comorbidities, which may be found in this same population such as diabetes, malnutrition, or end‐stage renal disease.3, 4 Most reported series have demonstrated a high mortality rate of invasive pulmonary aspergillosis in patients with COPD.14

The diagnosis of invasive pulmonary aspergillosis represents a significant clinical challenge. Diagnostic algorithms incorporating CT, antigen detection testing (for serum galactomannan and ‐glucan) as well as polymerase chain reaction diagnostic testing appear to be beneficial in the early diagnosis of invasive aspergillosis in particular settings such as in allogeneic hematopoietic stem cell transplantation.5 The role of antigen testing to identify early invasive aspergillosis in patients with COPD remains uncertain since it has been evaluated in a limited number of patients and therefore clinical suspicion is critical to push clinicians to pursue invasive tissue biopsy and cultures to confirm the diagnosis.3, 4

Based on the available clinical case series and in our case, invasive pulmonary aspergillosis should be suspected in COPD patients with rapidly progressive pneumonia not responding to antibacterial therapy and who have received oral or inhaled glucocorticoids in the recent past. In addition, this case also illustrates that occasionally, patients present with more than 1 life‐threatening diagnosis. This patient was also diagnosed with PE despite adequate prophylaxis. In addition to the well‐known clinical risk factors of obesity and lung disease, the underlying infection may have contributed to a systemic or local hypercoagulable condition that further increased her risk for venous thromboembolism.

KEY TEACHING POINTS

• Clinicians should remember to consider a broad differential in patients presenting with pneumonia, including the possibility of fungal pathogens in patients with known risk factors and in patients with multiple, potentially immunosuppressive comorbidities, or in patients who do not improve on standard antibiotic therapy.

• There is some evidence of an association between COPD and invasive aspergillosis, likely due to the frequent use of oral corticosteroids and/or chronic inhaled steroids in this population.

A 71‐year‐old African‐American woman presented to the emergency department with chest pain, shortness of breath, and cough. She had initially presented to her primary care physician 2 weeks previously complaining of worsening cough and shortness of breath and was told to continue her inhaled albuterol and glucocorticoids and was prescribed a prednisone taper and an unknown course of antibiotics. She noted no improvement in her symptoms despite compliance with this treatment. Three days prior to admission she described the gradual onset of left‐sided pleuritic chest pain with continued cough, associated with yellow sputum and worsening dyspnea. Review of systems was remarkable for generalized weakness and malaise. She denied fever, chills, orthopnea, paroxysmal nocturnal dyspnea, lower extremity edema, diarrhea, nausea, vomiting, or abdominal pain.

Her past medical history included a diagnosis of chronic obstructive pulmonary disease (COPD) but pulmonary function tests 7 years prior to admission showed an forced expiratory volume in the first second (FEV1)/forced vital capacity (FVC) ratio of 81%. She had a 30 pack‐year history of smoking, but quit 35 years ago. The patient also carried a diagnosis of heart failure, but an echocardiogram done 1 year ago demonstrated a left ventricular ejection fraction of 65% to 70% without diastolic dysfunction but mild right ventricular dilation and hypertrophy. Additionally, she had known nonobstructive coronary atherosclerotic heart disease, dyslipidemia, hypertension, morbid obesity, depression, and a documented chronic right hemidiaphragm elevation.

At this point the history suggests that the patient does not have a clear diagnosis of COPD. The lack of definitive spirometry evidence of chronic airway obstruction concerns me; I think that she may have been mistakenly treated with chronic inhaled steroids and doses of antibiotics for an acute exacerbation of chronic lung disease. Additional review of her history gives some indication of advanced lung disease, with her recent echocardiogram showing strain on the right ventricle with right ventricular hypertrophy and dilation, but there is no mention of the presence or severity of pulmonary hypertension. Nonetheless, I would be concerned that she probably has underlying significant cor pulmonale.

The patient now re‐presents with a worsening of her pulmonary symptoms. Her left‐sided pleuritic pain would make me concerned that she had a pulmonary embolus (PE). This morbidly obese patient with new pulmonary symptoms, right ventricular strain on her previous echocardiogram, and a persistent elevated right hemidiaphragm suggests a presentation of another PE.

At this time I cannot rule out other common possibilities such as infectious pneumonia. If she does have pneumonia, I would be concerned she could be harboring a multidrug‐resistant bacterial infection given her recent course of antibiotics in addition to her use of both chronic inhaled and intermittent oral glucocorticoids.

After gathering the rest of her full medical history, I would focus my physical exam on looking for evidence of parenchymal lung disease, signs of pulmonary hypertension, and pneumonia.

Her surgical history includes a previous hysterectomy, cholecystectomy, hernia repair, and left hepatic lobectomy for a benign mass. Her outpatient medications were ibuprofen, bupropion, fluvastatin, atenolol, potassium, aspirin, clopidogrel, albuterol inhaler, fluticasone/salmeterol inhaler, and omeprazole. She reports an allergy to penicillin and to sulfa drugs. Her mother died of an unknown cancer at age 77 years. She denied any international travel and she has always lived in Georgia.

The patient has been retired since 1992, having previously worked for the U.S. Postal Service. She admits to occasional alcohol intake (2 to 3 drinks a month). No recent travel, surgery, or prolonged immobilization was noted.

On initial examination she was alert and mentally appropriate, but appeared to be in mild respiratory distress with a respiratory rate of 28 breaths/minute. Her blood pressure (BP) was 99/70, heart rate 102, temperature of 38.2C, and oxygen saturation of 93% on room air and 97% on 2 L of oxygen via nasal cannula. Auscultation of her lungs revealed crackles over her left anterior lung field, bronchial breath sounds in the left posterior midlung, and bibasilar crackles. No wheezing was noted. Her cardiovascular exam and the remainder of her physical exam were unremarkable except for morbid obesity.

While my initial thoughts were leaning toward an exacerbation of chronic lung disease or possibly a new PE, at this moment, infection seems more likely. Indeed, her pulmonary findings suggest a left‐sided inflammatory process, and her vital signs meet criteria for systemic inflammatory response syndrome (SIRS). My primary concern is sepsis due to a drug‐resistant bacterial infection, including Staphylococcus aureus or gram‐negative bacteria or possibly more unusual organisms such as Nocardia or fungi, due to her recent use of antibiotics and chronic inhaled steroid use and recent course of oral glucocorticoids.

Conversely, the SIRS could be a manifestation of a noninfectious lung process such as acute interstitial pneumonia or an eosinophilic pneumonia. Given the diagnostic complexity, I would strongly consider consulting a pulmonologist if the patient did not improve quickly. At this point, I would like to review a posterior‐anterior (PA) and lateral chest radiograph, and room air arterial blood gas (ABG) in addition to basic laboratory test values.

Laboratory data obtained on admission was remarkable for a white blood cell (WBC) count of 26,500/L with 75% neutrophils and 6% eosinophils. Hemoglobin was 14.4 gm/dL. Platelet count was 454,000/L. Serum chemistries showed a sodium of 137 mEq/dL, potassium 4.3 mEq/dL, Cl 108 mEq/dL, bicarbonate 19 mEq/dL, blood urea nitrogen (BUN) 8 mg/dL, creatinine 1.0 mg/dL, and glucose 137 mg/dL. Cardiac enzymes were normal. Calcium was 9.8 mg/dL, albumin 2.7 gm/dL, total protein 6.9 gm/dL, AST 36 U/L, ALT 54 U/L and the bilirubin was normal. Chest radiograph (Figure 1) demonstrated a left perihilar infiltrate with air bronchograms and marked right hemidiaphragm elevation as seen on previous films. Unchanged increased interstitial markings were also present. Her electrocardiogram (ECG) showed normal sinus rhythm, normal axis, and QRS duration with nonspecific diffuse T‐wave abnormalities.

Figure 1

Given her presentation, I am worried about how well she is oxygenating and ventilating. An ABG should be done to assess her status more accurately. An albumin of 2.7 gm/dL indicates that she is fairly sick. I would not hesitate to consider testing the patient for human immunodeficiency virus (HIV) given how this information would dramatically change the differential diagnoses of her pulmonary process.

I am still most concerned about sepsis secondary to pneumonia in this patient with multiple chronic comorbidities, underlying chronic lung disease, receiving chronic inhaled glucocorticoids and a recent course of oral glucocorticoids and antibiotics. While I would initiate hydration I do not see a clear indication for early goal‐directed therapy for severe sepsis. In addition to obtaining an ABG and starting intravenous fluids, I would also draw blood cultures, send sputum for gram stain, culture, and sensitivity, and perform a urinalysis. I would also administer empiric antibiotics as quickly as possible based on a number of pneumonia clinical studies suggesting improved outcomes with early antibiotic administration. Because of her use of antibiotics and both inhaled and oral glucocorticoids, she is at higher risk for potentially multidrug‐resistant bacterial pathogens, including Staphyloccocus aureus and gram‐negative bacteria such as Pseudomonas and Klebsiella (Table 1). Therefore, I would initially cover her broadly for these organisms.

In addition to initial treatment choice, the inpatient triage decision is another important issue, especially at a community hospital where intensive care unit (ICU) resources are rare and often the admission decision is between sending a moderately sick patient to a regular floor bed or the medical ICU. Both the American Thoracic Society and Infectious Diseases Society of America support an ICU triage protocol in their guidelines for the management of community‐acquired pneumonia in adults that utilizes the following 9 minor criteria, of which the presence of at least 3 should support ICU admission: respiratory rate 30 breaths/minute; oxygenation index (pressure of oxygen [PaO₂]/fraction of inspired oxygen [FiO₂] ratio) 250; multilobar infiltrates; confusion/disorientation; uremia (BUN level 20 mg/dL); leukopenia (WBC count <4,000 cells/mm³); thrombocytopenia (platelet count <100,000 cells/mm³); hypothermia (core temperature <36C); and hypotension requiring aggressive fluid. Despite the absence of these criteria in this patient, it is important to note that no triage protocol has been adequately prospectively validated. Retrospective study of the minor criteria has found that the presence of at least 2 of the following 3 clinical criteria to have the highest specificity for predicting cardiopulmonary decompensation and subsequent need for ICU care: (1) initial hypotension (BP <90/60) on presentation with response to initial intravenous fluids to a BP >90/60; (2) oxygenation failure as indicated by PaO₂/FiO₂ ratio less than 250; or (3) the presence of multilobar or bilateral infiltrates on chest radiography.

I also want to comment on the relative elevation of her calcium, especially given the low albumin. This may simply be due to volume depletion, as many older patients have asymptomatic mild primary hyperparathyroidism. However, this elevated calcium may be a clue to the underlying lung process. Granulomatous lung disease due to tuberculosis or fungal infection could yield elevated calcium levels via increases in macrophage production of the active vitamin D metabolite calcitriol. This will need to be followed and a parathormone (PTH) level would be the best first test to request if the calcium level remains elevated. If the PTH level is suppressed, granulomatous disease or malignancy would be the more likely cause.

The patient was admitted with a presumptive diagnosis of community‐acquired pneumonia, was started on ceftriaxone and azithromycin, and given intravenous fluids, oxygen, and continued on inhaled salmeterol/fluticasone. Sputum was ordered for gram stain, culture, and sensitivity, and blood cultures were obtained. Urinalysis showed 1‐5 WBCs/high‐power field. Venous thromboembolism prophylaxis was initiated with subcutaneous heparin 5,000 units 8 hours. Her blood pressure normalized rapidly and during the next few days she stated she was feeling better. Despite continued significant wheezing her oxygen saturation remained at 98% on 2 L of oxygen via nasal cannula and she was less tachypneic. Attempts at obtaining an ABG were unsuccessful, and the patient subsequently refused additional attempts. Over the first few days her WBC count remained elevated above 20,000/L, with worsening bandemia (11%), and fever ranging from 38C to 39C. Sputum analysis was initially unsuccessful and blood cultures remained negative.

I am concerned about the persistent fever and elevated WBC count, and want to emphasize that I might have treated her with broader spectrum antibiotics to cover additional multidrug‐resistant bacterial organisms. I would have initially ordered vancomycin to cover methicillin resistant Staphylococcus aureus (MRSA) plus 2 additional antibiotics that cover multidrug‐resistant gram negative pathogens including Pseudomonas aeruginosa.

On the fifth hospital day, her WBC count dropped to 13,400/L and she defervesced. However, her respiratory status worsened during that same day with increased tachypnea. Of note, no results were reported from the initial sputum cultures and they were reordered and a noncontrast chest computed tomography (CT) was also ordered.

I think at this point, even though she has remained stable hemodynamically and oxygenating easily with supplemental oxygen, the question of whether or not her primary process is infectious or noninfectious lingers. I agree with obtaining a chest CT scan.

I am not surprised that sputum was not evaluated despite the orders. Among hospitalized patients with pneumonia, we frequently find that about a third of the time sputum cannot be obtained, about a third of the time it is obtained but the quality is unsatisfactory, and only a third of the time does the sputum sample meet criteria (less than 5 squamous epithelial cells per high‐power field) for adequate interpretation of the gram‐stain and culture result. Unfortunately, no one has developed a better way to improve this process. Nonetheless, I believe we do not try hard enough to obtain sputum in the first hours of evaluating our patients. I joke with our internal medicine residents that they should carry a sputum cup with them when they evaluate a patient with possible pneumonia. One recent prospective study of the value of sputum gram‐staining in community‐acquired pneumonia has found it to be highly specific for identifying Streptococcus pneumoniae or Haemophilus influenzae pneumonia.

The CT scan (Figure 2) performed on hospital day 6 demonstrated consolidation in the left upper lobe with areas of cavitation. There was also interstitial infiltrate extending into the lingula. Elevation of the right hemidiaphragm with atelectasis in both lung bases was also noted. A small effusion was present on the left and possibly a minimal effusion on the right as well. There was no pericardial effusion and only a few small pretracheal and periaortic lymph nodes were noted.

Figure 2

Given her failure to improve significantly after 6 days of antibiotic treatment, and her recent use of glucocorticoids, I would expand my diagnostic considerations to include other necrotizing bacterial infections, tuberculosis, fungus, and Nocardia.

Given the results of the CT scan she was placed in respiratory isolation to rule out active pulmonary tuberculosis. Though tachypneic, her blood pressure and pulse remained stable. However, her oxygen saturation deteriorated, declining to 92% on 2 L of oxygen via nasal cannula during hospital days 6 and 7. Subsequent successful attempts at collecting sputum yielded rapid growth of yeast (not Cryptococcus spp.). Pulmonary and infectious disease consultations were obtained and vancomycin was added to her regimen. The patient subsequently agreed to undergo diagnostic bronchoscopy.

I agree with obtaining input from expert consultants. I think we too often underutilize consultation in patients that are better but not completely better when we are not entirely sure what is going on. Evidence of noncryptococcus yeast in sputum may sometimes indicate colonization with Candida spp. without any significant clinical consequence. This finding may alternatively suggest the possibility of a true fungal pneumonia caused by 1 of the dimorphic fungi, including Histoplasma capsulatum, Paracoccidioides brasiliensis, Blastomyces dermatitides, or Coccidioides immitis. However, in this case there is not a strong epidemiologic patient history of exposure to any of these types of fungi.

Three sputum smears were negative for acid fast bacilli (AFB). Bronchoscopy revealed grossly abnormal mucosa in the left upper lobe and bronchomalacia, but no obstructive lesions. A transthoracic echocardiogram was ordered to evaluate her degree of pulmonary hypertension.

The 3 sputum specimens that were negative for AFB despite cavitary lung disease have high sensitivity for ruling out pulmonary tuberculosis. In addition, given the absence of any bacterial pathogen isolated from these specimens, I would pursue the possibility of other potential fungal pathogens given the patient's subacute course, history of using inhaled and oral corticosteroids, sputum results, and the presence of a cavitary lesion on her CT scan images.

Cytologic examination of the bronchoalveolar lavage (BAL) sample showed a cell differential of 1% bands, 58% neutrophils, 9% lymphs, and 27% eosinophils. The routine postbronchoscopy chest radiograph showed complete opacification of the left lung. The patient's WBC count rose to 26,000/L but she remained afebrile. Echocardiogram was reported to be of very poor quality due to her obesity. The cardiologist reviewing the echocardiogram called the attending physicians and stated there was possibly something in the left pulmonary artery and aortic dissection could not be ruled out.

The presence of eosinophilia on BAL may be a very important clue as to what lung pathology she has. In fact, eosinophilia in this setting may indicate the possibility of parasitic or fungal infection of the lung, or inflammation of the airway associated to drug toxicity, asthma, or environmental toxin exposure. With this additional information, I am concerned that she may be harboring an atypical infection such as an invasive fungus. The echocardiogram results are unclear to me but will need to be clarified with additional testing.

The interpretation of the transbronchial biopsy specimen was limited but suggested invasive pseudomembranous tracheal bronchitis due to aspergillosis. The routine hematoxylin and eosin stain showed portions of alveolar lung tissue and some collapsed submucosal bronchial glands with relatively normal‐looking lung tissue but along the edge of the spaces were obvious fungal organisms. The Gomori's methenamine silver (GMS) stain suggested the presence of Aspergillus organisms (Figure 3). Fungal cultures were also negative for any of the other dimorphic fungi or for molds.

Figure 3

Despite the negative culture results, the overall clinical picture suggests a necrotizing pneumonia caused by an invasive Aspergillus affecting both the bronchial tree and the lower respiratory tract. Generally, necrotizing pneumonias usually have a slow response to antimicrobial therapy. Given the inherent difficulty in differentiating clearly between invasive and noninvasive disease based on a transbronchial biopsy specimen, initiating antifungal therapy for invasive aspergillosis is appropriate in this patient. This patient's recent use of oral glucocorticoids and chronic use of inhaled glucocorticoids are both potential risk factors that predisposed this patient to develop invasive aspergillosis.

Many times we simply follow treatment guidelines for different categories of pneumonia, and have limited or inadequate clinical information to make more definitive diagnoses. While we need these treatment protocols, physicians must avoid falling into the trap that antibiotics treat all infectious etiologies in the lung and we should make reasonable efforts to pin down the etiology. All of us have been fooled by atypical presentations of tuberculosis, fungus, and noninfectious diseases of the lung. I think it behooves us to be vigilant about alternative diagnoses and consider pursuing additional studies whenever the clinical response to initial treatment does not meet our expectations.

Subsequently, the patient's additional cultures remained negative. The official echocardiogram report was read as questionable PE in the pulmonary artery. A spiral CT angiogram revealed a pulmonary artery embolus in the left upper lobe and she was treated with anticoagulation. Her shortness of breath improved steadily and she was successfully discharged after receiving 9 days of oral voriconazole. Outpatient pulmonary function testing documented the presence of chronic obstructive lung disease. She completed a 5‐month course of voriconazole therapy with significant clinical and radiologic improvement of her pulmonary infiltrate. She also completed a 12‐month treatment with warfarin for the concomitant pulmonary embolism. On follow‐up at 12 months she was doing well.

COMMENTARY

Aspergillosis caused particularly by Aspergillus fumigatus is considered an emerging infectious disease that frequently produces significant morbidity and mortality among immunocompromised patients.1, 2 The most frequently‐affected organs by this fungal pathogen include the lung and the central nervous system. There are 3 pathogenic mechanisms of Aspergillus infection of the lung: colonization, hypersensitivity reaction, and invasive aspergillosis.1

Invasive pulmonary aspergillosis is predominantly seen among individuals with severe degrees of immunosuppression as a result of solid‐organ transplantation, immunosuppressive therapies for autoimmune diseases, systemic glucocorticoids, and chemotherapy for hematologic malignancies. Mortality due to invasive aspergillosis continues to be very high (>58%) despite our improved ability to diagnose this condition and newer therapies to treat immunocompromised individuals.1 Invasive aspergillosis can manifest clinically in multiple ways. These include: (1) an invasive vascular process in which fungal organisms invade blood vessels, causing a rapidly progressive and often fatal illness; (2) necrotizing pseudomembranous tracheal bronchitis; (3) chronic necrotizing aspergillosis; (4) bronchopleural fistula; or (5) empyema.35 In our case, while the pathologic findings were most suggestive of an invasive pseudomembranous tracheal bronchitis, the overall clinical picture was most compatible with a necrotizing pneumonia due to invasive aspergillosis.

In addition to the traditional identified risk factors for invasive pulmonary aspergillosis, a number of reports during the last decade have demonstrated the occurrence of invasive aspergillosis in patients with COPD.14 A systematic review of the literature demonstrated that among 1,941 patients with invasive aspergillosis, 26 (1.3%) had evidence of COPD as the main risk factor for developing invasive aspergillosis.1 A single report has associated the potential use of inhaled steroids with the occurrence of invasive aspergillosis in this patient population.2 However, other factors that may promote increased susceptibility to invasive fungal infection among patients with COPD include the use of long‐term or repeated short‐term glucocorticoid treatments, and the presence of multiple additional comorbidities, which may be found in this same population such as diabetes, malnutrition, or end‐stage renal disease.3, 4 Most reported series have demonstrated a high mortality rate of invasive pulmonary aspergillosis in patients with COPD.14

The diagnosis of invasive pulmonary aspergillosis represents a significant clinical challenge. Diagnostic algorithms incorporating CT, antigen detection testing (for serum galactomannan and ‐glucan) as well as polymerase chain reaction diagnostic testing appear to be beneficial in the early diagnosis of invasive aspergillosis in particular settings such as in allogeneic hematopoietic stem cell transplantation.5 The role of antigen testing to identify early invasive aspergillosis in patients with COPD remains uncertain since it has been evaluated in a limited number of patients and therefore clinical suspicion is critical to push clinicians to pursue invasive tissue biopsy and cultures to confirm the diagnosis.3, 4

Based on the available clinical case series and in our case, invasive pulmonary aspergillosis should be suspected in COPD patients with rapidly progressive pneumonia not responding to antibacterial therapy and who have received oral or inhaled glucocorticoids in the recent past. In addition, this case also illustrates that occasionally, patients present with more than 1 life‐threatening diagnosis. This patient was also diagnosed with PE despite adequate prophylaxis. In addition to the well‐known clinical risk factors of obesity and lung disease, the underlying infection may have contributed to a systemic or local hypercoagulable condition that further increased her risk for venous thromboembolism.

KEY TEACHING POINTS

• Clinicians should remember to consider a broad differential in patients presenting with pneumonia, including the possibility of fungal pathogens in patients with known risk factors and in patients with multiple, potentially immunosuppressive comorbidities, or in patients who do not improve on standard antibiotic therapy.

• There is some evidence of an association between COPD and invasive aspergillosis, likely due to the frequent use of oral corticosteroids and/or chronic inhaled steroids in this population.

A 71‐year‐old African‐American woman presented to the emergency department with chest pain, shortness of breath, and cough. She had initially presented to her primary care physician 2 weeks previously complaining of worsening cough and shortness of breath and was told to continue her inhaled albuterol and glucocorticoids and was prescribed a prednisone taper and an unknown course of antibiotics. She noted no improvement in her symptoms despite compliance with this treatment. Three days prior to admission she described the gradual onset of left‐sided pleuritic chest pain with continued cough, associated with yellow sputum and worsening dyspnea. Review of systems was remarkable for generalized weakness and malaise. She denied fever, chills, orthopnea, paroxysmal nocturnal dyspnea, lower extremity edema, diarrhea, nausea, vomiting, or abdominal pain.

Her past medical history included a diagnosis of chronic obstructive pulmonary disease (COPD) but pulmonary function tests 7 years prior to admission showed an forced expiratory volume in the first second (FEV1)/forced vital capacity (FVC) ratio of 81%. She had a 30 pack‐year history of smoking, but quit 35 years ago. The patient also carried a diagnosis of heart failure, but an echocardiogram done 1 year ago demonstrated a left ventricular ejection fraction of 65% to 70% without diastolic dysfunction but mild right ventricular dilation and hypertrophy. Additionally, she had known nonobstructive coronary atherosclerotic heart disease, dyslipidemia, hypertension, morbid obesity, depression, and a documented chronic right hemidiaphragm elevation.

At this point the history suggests that the patient does not have a clear diagnosis of COPD. The lack of definitive spirometry evidence of chronic airway obstruction concerns me; I think that she may have been mistakenly treated with chronic inhaled steroids and doses of antibiotics for an acute exacerbation of chronic lung disease. Additional review of her history gives some indication of advanced lung disease, with her recent echocardiogram showing strain on the right ventricle with right ventricular hypertrophy and dilation, but there is no mention of the presence or severity of pulmonary hypertension. Nonetheless, I would be concerned that she probably has underlying significant cor pulmonale.

The patient now re‐presents with a worsening of her pulmonary symptoms. Her left‐sided pleuritic pain would make me concerned that she had a pulmonary embolus (PE). This morbidly obese patient with new pulmonary symptoms, right ventricular strain on her previous echocardiogram, and a persistent elevated right hemidiaphragm suggests a presentation of another PE.

At this time I cannot rule out other common possibilities such as infectious pneumonia. If she does have pneumonia, I would be concerned she could be harboring a multidrug‐resistant bacterial infection given her recent course of antibiotics in addition to her use of both chronic inhaled and intermittent oral glucocorticoids.

After gathering the rest of her full medical history, I would focus my physical exam on looking for evidence of parenchymal lung disease, signs of pulmonary hypertension, and pneumonia.

Her surgical history includes a previous hysterectomy, cholecystectomy, hernia repair, and left hepatic lobectomy for a benign mass. Her outpatient medications were ibuprofen, bupropion, fluvastatin, atenolol, potassium, aspirin, clopidogrel, albuterol inhaler, fluticasone/salmeterol inhaler, and omeprazole. She reports an allergy to penicillin and to sulfa drugs. Her mother died of an unknown cancer at age 77 years. She denied any international travel and she has always lived in Georgia.

The patient has been retired since 1992, having previously worked for the U.S. Postal Service. She admits to occasional alcohol intake (2 to 3 drinks a month). No recent travel, surgery, or prolonged immobilization was noted.

On initial examination she was alert and mentally appropriate, but appeared to be in mild respiratory distress with a respiratory rate of 28 breaths/minute. Her blood pressure (BP) was 99/70, heart rate 102, temperature of 38.2C, and oxygen saturation of 93% on room air and 97% on 2 L of oxygen via nasal cannula. Auscultation of her lungs revealed crackles over her left anterior lung field, bronchial breath sounds in the left posterior midlung, and bibasilar crackles. No wheezing was noted. Her cardiovascular exam and the remainder of her physical exam were unremarkable except for morbid obesity.

While my initial thoughts were leaning toward an exacerbation of chronic lung disease or possibly a new PE, at this moment, infection seems more likely. Indeed, her pulmonary findings suggest a left‐sided inflammatory process, and her vital signs meet criteria for systemic inflammatory response syndrome (SIRS). My primary concern is sepsis due to a drug‐resistant bacterial infection, including Staphylococcus aureus or gram‐negative bacteria or possibly more unusual organisms such as Nocardia or fungi, due to her recent use of antibiotics and chronic inhaled steroid use and recent course of oral glucocorticoids.

Conversely, the SIRS could be a manifestation of a noninfectious lung process such as acute interstitial pneumonia or an eosinophilic pneumonia. Given the diagnostic complexity, I would strongly consider consulting a pulmonologist if the patient did not improve quickly. At this point, I would like to review a posterior‐anterior (PA) and lateral chest radiograph, and room air arterial blood gas (ABG) in addition to basic laboratory test values.

Laboratory data obtained on admission was remarkable for a white blood cell (WBC) count of 26,500/L with 75% neutrophils and 6% eosinophils. Hemoglobin was 14.4 gm/dL. Platelet count was 454,000/L. Serum chemistries showed a sodium of 137 mEq/dL, potassium 4.3 mEq/dL, Cl 108 mEq/dL, bicarbonate 19 mEq/dL, blood urea nitrogen (BUN) 8 mg/dL, creatinine 1.0 mg/dL, and glucose 137 mg/dL. Cardiac enzymes were normal. Calcium was 9.8 mg/dL, albumin 2.7 gm/dL, total protein 6.9 gm/dL, AST 36 U/L, ALT 54 U/L and the bilirubin was normal. Chest radiograph (Figure 1) demonstrated a left perihilar infiltrate with air bronchograms and marked right hemidiaphragm elevation as seen on previous films. Unchanged increased interstitial markings were also present. Her electrocardiogram (ECG) showed normal sinus rhythm, normal axis, and QRS duration with nonspecific diffuse T‐wave abnormalities.

Figure 1

Given her presentation, I am worried about how well she is oxygenating and ventilating. An ABG should be done to assess her status more accurately. An albumin of 2.7 gm/dL indicates that she is fairly sick. I would not hesitate to consider testing the patient for human immunodeficiency virus (HIV) given how this information would dramatically change the differential diagnoses of her pulmonary process.

I am still most concerned about sepsis secondary to pneumonia in this patient with multiple chronic comorbidities, underlying chronic lung disease, receiving chronic inhaled glucocorticoids and a recent course of oral glucocorticoids and antibiotics. While I would initiate hydration I do not see a clear indication for early goal‐directed therapy for severe sepsis. In addition to obtaining an ABG and starting intravenous fluids, I would also draw blood cultures, send sputum for gram stain, culture, and sensitivity, and perform a urinalysis. I would also administer empiric antibiotics as quickly as possible based on a number of pneumonia clinical studies suggesting improved outcomes with early antibiotic administration. Because of her use of antibiotics and both inhaled and oral glucocorticoids, she is at higher risk for potentially multidrug‐resistant bacterial pathogens, including Staphyloccocus aureus and gram‐negative bacteria such as Pseudomonas and Klebsiella (Table 1). Therefore, I would initially cover her broadly for these organisms.

In addition to initial treatment choice, the inpatient triage decision is another important issue, especially at a community hospital where intensive care unit (ICU) resources are rare and often the admission decision is between sending a moderately sick patient to a regular floor bed or the medical ICU. Both the American Thoracic Society and Infectious Diseases Society of America support an ICU triage protocol in their guidelines for the management of community‐acquired pneumonia in adults that utilizes the following 9 minor criteria, of which the presence of at least 3 should support ICU admission: respiratory rate 30 breaths/minute; oxygenation index (pressure of oxygen [PaO₂]/fraction of inspired oxygen [FiO₂] ratio) 250; multilobar infiltrates; confusion/disorientation; uremia (BUN level 20 mg/dL); leukopenia (WBC count <4,000 cells/mm³); thrombocytopenia (platelet count <100,000 cells/mm³); hypothermia (core temperature <36C); and hypotension requiring aggressive fluid. Despite the absence of these criteria in this patient, it is important to note that no triage protocol has been adequately prospectively validated. Retrospective study of the minor criteria has found that the presence of at least 2 of the following 3 clinical criteria to have the highest specificity for predicting cardiopulmonary decompensation and subsequent need for ICU care: (1) initial hypotension (BP <90/60) on presentation with response to initial intravenous fluids to a BP >90/60; (2) oxygenation failure as indicated by PaO₂/FiO₂ ratio less than 250; or (3) the presence of multilobar or bilateral infiltrates on chest radiography.

I also want to comment on the relative elevation of her calcium, especially given the low albumin. This may simply be due to volume depletion, as many older patients have asymptomatic mild primary hyperparathyroidism. However, this elevated calcium may be a clue to the underlying lung process. Granulomatous lung disease due to tuberculosis or fungal infection could yield elevated calcium levels via increases in macrophage production of the active vitamin D metabolite calcitriol. This will need to be followed and a parathormone (PTH) level would be the best first test to request if the calcium level remains elevated. If the PTH level is suppressed, granulomatous disease or malignancy would be the more likely cause.

The patient was admitted with a presumptive diagnosis of community‐acquired pneumonia, was started on ceftriaxone and azithromycin, and given intravenous fluids, oxygen, and continued on inhaled salmeterol/fluticasone. Sputum was ordered for gram stain, culture, and sensitivity, and blood cultures were obtained. Urinalysis showed 1‐5 WBCs/high‐power field. Venous thromboembolism prophylaxis was initiated with subcutaneous heparin 5,000 units 8 hours. Her blood pressure normalized rapidly and during the next few days she stated she was feeling better. Despite continued significant wheezing her oxygen saturation remained at 98% on 2 L of oxygen via nasal cannula and she was less tachypneic. Attempts at obtaining an ABG were unsuccessful, and the patient subsequently refused additional attempts. Over the first few days her WBC count remained elevated above 20,000/L, with worsening bandemia (11%), and fever ranging from 38C to 39C. Sputum analysis was initially unsuccessful and blood cultures remained negative.

I am concerned about the persistent fever and elevated WBC count, and want to emphasize that I might have treated her with broader spectrum antibiotics to cover additional multidrug‐resistant bacterial organisms. I would have initially ordered vancomycin to cover methicillin resistant Staphylococcus aureus (MRSA) plus 2 additional antibiotics that cover multidrug‐resistant gram negative pathogens including Pseudomonas aeruginosa.

On the fifth hospital day, her WBC count dropped to 13,400/L and she defervesced. However, her respiratory status worsened during that same day with increased tachypnea. Of note, no results were reported from the initial sputum cultures and they were reordered and a noncontrast chest computed tomography (CT) was also ordered.

I think at this point, even though she has remained stable hemodynamically and oxygenating easily with supplemental oxygen, the question of whether or not her primary process is infectious or noninfectious lingers. I agree with obtaining a chest CT scan.

I am not surprised that sputum was not evaluated despite the orders. Among hospitalized patients with pneumonia, we frequently find that about a third of the time sputum cannot be obtained, about a third of the time it is obtained but the quality is unsatisfactory, and only a third of the time does the sputum sample meet criteria (less than 5 squamous epithelial cells per high‐power field) for adequate interpretation of the gram‐stain and culture result. Unfortunately, no one has developed a better way to improve this process. Nonetheless, I believe we do not try hard enough to obtain sputum in the first hours of evaluating our patients. I joke with our internal medicine residents that they should carry a sputum cup with them when they evaluate a patient with possible pneumonia. One recent prospective study of the value of sputum gram‐staining in community‐acquired pneumonia has found it to be highly specific for identifying Streptococcus pneumoniae or Haemophilus influenzae pneumonia.

The CT scan (Figure 2) performed on hospital day 6 demonstrated consolidation in the left upper lobe with areas of cavitation. There was also interstitial infiltrate extending into the lingula. Elevation of the right hemidiaphragm with atelectasis in both lung bases was also noted. A small effusion was present on the left and possibly a minimal effusion on the right as well. There was no pericardial effusion and only a few small pretracheal and periaortic lymph nodes were noted.

Figure 2

Given her failure to improve significantly after 6 days of antibiotic treatment, and her recent use of glucocorticoids, I would expand my diagnostic considerations to include other necrotizing bacterial infections, tuberculosis, fungus, and Nocardia.

Given the results of the CT scan she was placed in respiratory isolation to rule out active pulmonary tuberculosis. Though tachypneic, her blood pressure and pulse remained stable. However, her oxygen saturation deteriorated, declining to 92% on 2 L of oxygen via nasal cannula during hospital days 6 and 7. Subsequent successful attempts at collecting sputum yielded rapid growth of yeast (not Cryptococcus spp.). Pulmonary and infectious disease consultations were obtained and vancomycin was added to her regimen. The patient subsequently agreed to undergo diagnostic bronchoscopy.

I agree with obtaining input from expert consultants. I think we too often underutilize consultation in patients that are better but not completely better when we are not entirely sure what is going on. Evidence of noncryptococcus yeast in sputum may sometimes indicate colonization with Candida spp. without any significant clinical consequence. This finding may alternatively suggest the possibility of a true fungal pneumonia caused by 1 of the dimorphic fungi, including Histoplasma capsulatum, Paracoccidioides brasiliensis, Blastomyces dermatitides, or Coccidioides immitis. However, in this case there is not a strong epidemiologic patient history of exposure to any of these types of fungi.

Three sputum smears were negative for acid fast bacilli (AFB). Bronchoscopy revealed grossly abnormal mucosa in the left upper lobe and bronchomalacia, but no obstructive lesions. A transthoracic echocardiogram was ordered to evaluate her degree of pulmonary hypertension.

The 3 sputum specimens that were negative for AFB despite cavitary lung disease have high sensitivity for ruling out pulmonary tuberculosis. In addition, given the absence of any bacterial pathogen isolated from these specimens, I would pursue the possibility of other potential fungal pathogens given the patient's subacute course, history of using inhaled and oral corticosteroids, sputum results, and the presence of a cavitary lesion on her CT scan images.

Cytologic examination of the bronchoalveolar lavage (BAL) sample showed a cell differential of 1% bands, 58% neutrophils, 9% lymphs, and 27% eosinophils. The routine postbronchoscopy chest radiograph showed complete opacification of the left lung. The patient's WBC count rose to 26,000/L but she remained afebrile. Echocardiogram was reported to be of very poor quality due to her obesity. The cardiologist reviewing the echocardiogram called the attending physicians and stated there was possibly something in the left pulmonary artery and aortic dissection could not be ruled out.

The presence of eosinophilia on BAL may be a very important clue as to what lung pathology she has. In fact, eosinophilia in this setting may indicate the possibility of parasitic or fungal infection of the lung, or inflammation of the airway associated to drug toxicity, asthma, or environmental toxin exposure. With this additional information, I am concerned that she may be harboring an atypical infection such as an invasive fungus. The echocardiogram results are unclear to me but will need to be clarified with additional testing.

The interpretation of the transbronchial biopsy specimen was limited but suggested invasive pseudomembranous tracheal bronchitis due to aspergillosis. The routine hematoxylin and eosin stain showed portions of alveolar lung tissue and some collapsed submucosal bronchial glands with relatively normal‐looking lung tissue but along the edge of the spaces were obvious fungal organisms. The Gomori's methenamine silver (GMS) stain suggested the presence of Aspergillus organisms (Figure 3). Fungal cultures were also negative for any of the other dimorphic fungi or for molds.

Figure 3

Despite the negative culture results, the overall clinical picture suggests a necrotizing pneumonia caused by an invasive Aspergillus affecting both the bronchial tree and the lower respiratory tract. Generally, necrotizing pneumonias usually have a slow response to antimicrobial therapy. Given the inherent difficulty in differentiating clearly between invasive and noninvasive disease based on a transbronchial biopsy specimen, initiating antifungal therapy for invasive aspergillosis is appropriate in this patient. This patient's recent use of oral glucocorticoids and chronic use of inhaled glucocorticoids are both potential risk factors that predisposed this patient to develop invasive aspergillosis.

Many times we simply follow treatment guidelines for different categories of pneumonia, and have limited or inadequate clinical information to make more definitive diagnoses. While we need these treatment protocols, physicians must avoid falling into the trap that antibiotics treat all infectious etiologies in the lung and we should make reasonable efforts to pin down the etiology. All of us have been fooled by atypical presentations of tuberculosis, fungus, and noninfectious diseases of the lung. I think it behooves us to be vigilant about alternative diagnoses and consider pursuing additional studies whenever the clinical response to initial treatment does not meet our expectations.

Subsequently, the patient's additional cultures remained negative. The official echocardiogram report was read as questionable PE in the pulmonary artery. A spiral CT angiogram revealed a pulmonary artery embolus in the left upper lobe and she was treated with anticoagulation. Her shortness of breath improved steadily and she was successfully discharged after receiving 9 days of oral voriconazole. Outpatient pulmonary function testing documented the presence of chronic obstructive lung disease. She completed a 5‐month course of voriconazole therapy with significant clinical and radiologic improvement of her pulmonary infiltrate. She also completed a 12‐month treatment with warfarin for the concomitant pulmonary embolism. On follow‐up at 12 months she was doing well.

COMMENTARY

Aspergillosis caused particularly by Aspergillus fumigatus is considered an emerging infectious disease that frequently produces significant morbidity and mortality among immunocompromised patients.1, 2 The most frequently‐affected organs by this fungal pathogen include the lung and the central nervous system. There are 3 pathogenic mechanisms of Aspergillus infection of the lung: colonization, hypersensitivity reaction, and invasive aspergillosis.1

Invasive pulmonary aspergillosis is predominantly seen among individuals with severe degrees of immunosuppression as a result of solid‐organ transplantation, immunosuppressive therapies for autoimmune diseases, systemic glucocorticoids, and chemotherapy for hematologic malignancies. Mortality due to invasive aspergillosis continues to be very high (>58%) despite our improved ability to diagnose this condition and newer therapies to treat immunocompromised individuals.1 Invasive aspergillosis can manifest clinically in multiple ways. These include: (1) an invasive vascular process in which fungal organisms invade blood vessels, causing a rapidly progressive and often fatal illness; (2) necrotizing pseudomembranous tracheal bronchitis; (3) chronic necrotizing aspergillosis; (4) bronchopleural fistula; or (5) empyema.35 In our case, while the pathologic findings were most suggestive of an invasive pseudomembranous tracheal bronchitis, the overall clinical picture was most compatible with a necrotizing pneumonia due to invasive aspergillosis.

In addition to the traditional identified risk factors for invasive pulmonary aspergillosis, a number of reports during the last decade have demonstrated the occurrence of invasive aspergillosis in patients with COPD.14 A systematic review of the literature demonstrated that among 1,941 patients with invasive aspergillosis, 26 (1.3%) had evidence of COPD as the main risk factor for developing invasive aspergillosis.1 A single report has associated the potential use of inhaled steroids with the occurrence of invasive aspergillosis in this patient population.2 However, other factors that may promote increased susceptibility to invasive fungal infection among patients with COPD include the use of long‐term or repeated short‐term glucocorticoid treatments, and the presence of multiple additional comorbidities, which may be found in this same population such as diabetes, malnutrition, or end‐stage renal disease.3, 4 Most reported series have demonstrated a high mortality rate of invasive pulmonary aspergillosis in patients with COPD.14

The diagnosis of invasive pulmonary aspergillosis represents a significant clinical challenge. Diagnostic algorithms incorporating CT, antigen detection testing (for serum galactomannan and ‐glucan) as well as polymerase chain reaction diagnostic testing appear to be beneficial in the early diagnosis of invasive aspergillosis in particular settings such as in allogeneic hematopoietic stem cell transplantation.5 The role of antigen testing to identify early invasive aspergillosis in patients with COPD remains uncertain since it has been evaluated in a limited number of patients and therefore clinical suspicion is critical to push clinicians to pursue invasive tissue biopsy and cultures to confirm the diagnosis.3, 4

Based on the available clinical case series and in our case, invasive pulmonary aspergillosis should be suspected in COPD patients with rapidly progressive pneumonia not responding to antibacterial therapy and who have received oral or inhaled glucocorticoids in the recent past. In addition, this case also illustrates that occasionally, patients present with more than 1 life‐threatening diagnosis. This patient was also diagnosed with PE despite adequate prophylaxis. In addition to the well‐known clinical risk factors of obesity and lung disease, the underlying infection may have contributed to a systemic or local hypercoagulable condition that further increased her risk for venous thromboembolism.

KEY TEACHING POINTS

• Clinicians should remember to consider a broad differential in patients presenting with pneumonia, including the possibility of fungal pathogens in patients with known risk factors and in patients with multiple, potentially immunosuppressive comorbidities, or in patients who do not improve on standard antibiotic therapy.

• There is some evidence of an association between COPD and invasive aspergillosis, likely due to the frequent use of oral corticosteroids and/or chronic inhaled steroids in this population.

A 36 year‐old male physician was admitted to a Baltimore hospital in April 1907 with weight loss, weakness, arthralgias, and abdominal distension that had progressed over 5 years.

In 1907, major causes of unexplained weight loss included tuberculosis, hyperthyroidism, cancer, and diabetes. Arthralgias and weakness are not specific. The insidious progression over 5 years narrows the infectious possibilities; tuberculosis and syphilis are important considerations. Since surgical removal was the main treatment for malignancy in 1907, a history of prior surgery might point to a previously diagnosed malignancy that is now progressing.

Five years earlier, while visiting Turkey as a medical missionary, he first noted the onset of arthralgias that lasted 6 to 8 hours and occurred 3 to 4 times per week. Over time, these attacks lasted up to 24 hours and became associated with warmth, swelling, and tenderness of both small and large joints. He gradually lost weight and strength. One year prior to arrival in the hospital, he developed a cough productive of yellow sputum. Seven months prior, he returned from Turkey to Atlanta and noticed an increase in his cough, along with fevers of 100 Fahrenheit and night sweats.

The primacy of the arthralgias in this illness lead me to consider primary rheumatic diseases, and multisystem diseases (including infections) with a predominant skeletal component. In 1907, tests for lupus and the rheumatoid factor were not available. Neither skeletal remains nor works of art provide evidence that rheumatoid arthritis existed until the 19th century, whereas ankylosing spondylitis, gout, and rickets were present by then.

As a medical missionary, he might have acquired a disease endemic to the areas he visited, or the travel history may be a red herring. Familial Mediterranean fever, though prevalent in Turkey and a cause of arthralgias accompanied by recurrent attacks of abdominal pain and fever, is not an acquired disease. Behcet's disease, also known as Silk Trader's Route disease, is found in descendents of the countries that comprised the ancient Silk Route from Japan to the Middle East and may cause arthritis along with oral ulcers, genital lesions, pathergy or uveitis. I would inquire about his ancestry and fevers before dismissing these possibilities.

Although 5 years would be unusually long for tuberculosis to go unrecognized, a physician in the first half of the 20th century would place tuberculosis near the top of possible diagnoses. In 1930, a time when the population of the United States was considerably less, there were over 300,000 cases of tuberculosis. Physicians, and in particular pathologists since autopsies were more commonly performed, often died from tuberculosis since streptomycin, the first antituberculous medication, did not arrive until 1944. At the turn of the 20th century, the ability to detect tubercle bacilli was quite good. Thus, I would include tuberculous peritonitis as a cause of the progressive abdominal symptoms in this physician. In approximately one‐third of patients with tuberculous peritonitis there is evidence of pulmonary disease, and I would try to culture tuberculosis in samples of sputum, a test then so common it probably rivaled our frequent complete blood counts in popularity.

Six months prior, examinations of sputum were negative for tubercle bacilli. Four months prior to arrival, the patient moved to New Mexico. His cough improved but he continued to lose weight and had diarrhea consisting of 3 to 4 loose or semiformed bowel movements per day. Three months prior to admission, he noted an increase in abdominal girth along with right lower quadrant fullness. One month prior, he noted painful swelling and warmth in both ankles as well as dyspnea with exertion.

The increased abdominal girth in the context of chronic illness might be due to ascites, adenopathy, visceromegaly, or mass lesions such as a neoplasm or abscess. If ascites is the cause, one would need to consider primary hepatic disorders, as well as extrahepatic diseases that could progress over years. Infection with hepatitis A virus does not cause chronic liver disease. Hepatitis B, in those days, was referred to as serum hepatitis, and a serum marker for the B virusthe Australia antigenwas not identified until 1967. Cardiac causes of ascites include congestive heart failure and constrictive pericarditis, the latter an important consideration because it is potentially curable. Also, constrictive pericarditis can present as an indolent weight‐losing disease because of chronic visceral congestion. Other considerations include nephrotic syndrome, infection, and neoplasm, including mesothelioma.

Abdominal distention might also be seen with a smoldering abscess. In addition to an appendiceal process, the travel and right lower quadrant localization reminds us to consider ameboma. This patient surely was in an area where amebiasis was endemic, and amebomaa chronic inflammatory form of infection with E. histolytica not associated with diarrhea or liver cystsmay mimic cecal carcinoma. Exertional dyspnea suggests at least the possibility of cardiac disease. Despite the negative sputum cultures, tuberculosis remains high on the list as a cause of constrictive pericarditis or peritonitis, either of which may occur in the absence of active pulmonary disease.

Past medical history included measles and whooping cough as a child, mild pleurisy at age 14, mild influenza 7 years previously. The patient had a tonsillectomy as a child and had a portion of his inferior turbinate bone removed in an attempt to relieve a nasal condition.

On physical exam, the patient was thin and the skin over his face and hands was deep brown. His temperature was 101.5 Fahrenheit, the heart rate was 100, and the respiratory rate was 24. Small lymph nodes were palpable in the axillary and epitrochlear areas. His thorax moved asymmetrically, with less movement on the left apex and slight dullness to percussion in that area. The pulmonic component of the second heart sound was mildly accentuated. The abdomen displayed fullness and tympany, most pronounced in the right lower quadrant without hepatosplenomegaly. The left ankle was swollen, and the overlying skin was tense, shiny, and hot. On both lower legs, areas of discoloration and slight induration were observed, felt to be consistent with faded erythema nodosum.

Though pleurisy has numerous causes, its presence raises the specter of tuberculosis again. The nasal condition triggers thoughts of Wegener's granulomatosis or lethal midline granuloma, both unlikely diagnoses here. The pulmonary exam suggests an apical process, such as tuberculosis, and the accentuated pulmonic heart sound implies pulmonary hypertension, which could be due to a number of chronic pulmonary diseases. The epitrochlear nodes are of interest since lymphoma and Hodgkin's disease rarely involve this area; syphilis and human immunodeficiency virus (HIV) are a few of the chronic diseases that may involve this lymph node region. More helpful is the absence of hepatosplenomegaly, since many indolent malignancies and infections would be expected to enlarge these organs by this point.

Monoarticular arthritis is often due to infection, and less likely due to rheumatoid disease. When rheumatoid arthritis flares, the entire skeleton flares, not single joints. Given the indolence and this single joint involvement, tuberculosis again comes to mind.

I would next want to obtain a plain chest radiograph, looking for evidence of tuberculosis. As with any test, one should ask how this will change management. In 1907, antituberculous medications were not available, so therapy was directed at lowering oxygen tension in the primary site of infection; for example, pulmonary disease was addressed via pneumothorax. If the chest radiograph provides little hint of tuberculosis, then consideration must be given to exploratory surgery of the abdomen given the focal abnormality in the right lower quadrant.

A peripheral blood smear revealed a hypochromic microcytic anemia. The total red blood cell count was 4.468 million/mm³ (normal range for men is 4.52‐5.90 million/mm³), white blood cell count was 8180/mm³, including 80% granulocytes and 9% eosinophils. On gross inspection, the stool was clay‐colored, and stool microscopy demonstrated large numbers of neutral fat droplets, but no ova, parasites, or tubercle bacilli. Urinalysis revealed no albumin or casts, and the bones were normal on ankle radiographs. Another sample of sputum revealed no tubercle bacilli, and intradermal placement of tuberculin provoked no reaction.

His negative tuberculin skin reaction is unusual for that era, because of the prevalence of tuberculosis. Most likely, he is anergic because of his severe underlying illness, and the absent reaction is thus not all that helpful a clue. Multiple negative sputum examinations lower the possibility of pulmonary, but not extrapulmonary, tuberculosis. The absence of bony destruction on ankle radiographs lowers my suspicion for tuberculous arthritis.

The excess stool fat implies steatogenic diarrhea from malabsorption, and 2 categories here are pancreatic and luminal diseases. Of these 2, pancreatic etiologies produce more severe malabsorption. We do not hear mention of jaundice, however, and I cannot see how to link the pancreas to the arthritis. A chronic infection which may produce malabsorption and eosinophilia is strongyloidiasis, endemic in the southeastern United States. However, this patient did not manifest the most common finding of chronic strongyloidiasis, namely asthma. Adrenal insufficiency, as might result from disseminated tuberculosis, is associated with increased skin pigmentation, diarrhea, and eosinophilia. However, the diarrhea of adrenal insufficiency is not malabsorptive, and serum electrolytes and cortisol tests were not available then to confirm this diagnosis antemortem.

In an attempt to identify a unifying cause of chronic arthritis, malabsorption, and increased skin pigmentation, I must consider Whipple's disease first and foremost. Physicians then were strapped and observation was often the default mode of the day. Given the abdominal findings, an exploratory laparotomy would be warranted if his condition deteriorated.

Despite forced oral feedings, the patient continued to lose weight, from his normal of 175 pounds to a nadir of 145 pounds. Because of worsening abdominal distention, the patient underwent exploratory abdominal surgery on the twenty‐first hospital day. Intraoperatively, no ascites was seen, but his mesenteric lymph nodes were hard and markedly enlarged. The abdomen was closed without further intervention. Two days after the surgery, the patient abruptly developed dyspnea. His respirations were 40 per minute, heart rate was 120, and he had minimal rales at the lung bases without findings of consolidation. He died 2 hours later, on the twenty‐third hospital day, and an autopsy was performed.

The final event may have been a pulmonary embolism. As for the adenopathy, lymphoma and tuberculosis are possible. Heavy chain disease, an unusual lymphoproliferative disorder found in persons from the old Silk Trader's Route from the Middle East to the Orient, is a remote prospect. However, 5 years is just too indolent for most cancers and would be very unusual for tuberculosis. I think the findings support Whipple's disease, and I wonder if this was the first reported case.

On postmortem examination, the abdominal adenopathy was striking. The small intestine contained enlarged villi with thickened submucosa, and the mesenteric nodes were enlarged with fat deposits and abnormal foamy cells. Within these foamy cells, microscopy revealed numerous rod‐shaped organisms. All studies were negative for tuberculosis, and although the pathologist, Dr. George Hoyt Whipple, suspected an infectious etiology, he offered the name intestinal lipodystrophy to emphasize the striking small intestinal changes he witnessed at autopsy, and which are the hallmarks of the disease that now bears his name. Whipple also shared the 1934 Nobel Prize in Physiology or Medicine with Minot and Murphy for their discovery that a nutritional substance in liver, now known as vitamin B12, was beneficial in treating pernicious anemia.

COMMENTARY

This is the index case of Whipple's disease, summarized from the original 1907 description.1 George Hoyt Whipple, then a pathologist at Johns Hopkins, highlights the value of keen observation and a well‐done case report in describing a new disease entity. One of the roles of case reports is to detail the features of an unknown disease. In this capacity, Whipple's summary is exemplary. His achievement was having the openness of mind to realize he was witnessing something novel, and to take the first step on the road to discovery. Although Whipple suspected he was staring at a unique disease, he could not pinpoint the culprit bacteria and he had trouble squaring the extraintestinal findings with the marked intestinal anomalies. It was left to decades of input from others to confirm the association of arthralgias, eosinophilia, skin hyperpigmentation, and cardiac valve abnormalities with intestinal malabsorption, and to culture the infectious agent.

In his discussion, Whipple recognized he was confronted with a novel clinical entity. Prior to surgery, pulmonary and mesenteric tuberculosis were suspected, based on the fevers, weight loss, cough, fat malabsorption, and lymphadenopathy. However, he felt the left apical exam was more representative of retraction from prior disease than active infection. He was also bothered by the negative skin reaction and sputum tests. At surgery, the pronounced adenopathy suggested sarcoma or Hodgkin's disease but postmortem examination eliminated these possibilities. At autopsy, the abdominal findings were most striking. The small intestine demonstrated enlarged villi with thickened submucosa and markedly enlarged mesenteric lymph glands containing large fat deposits and distinctly abnormal foamy cells. These foamy macrophages contained great numbers of rod‐shaped organisms resembling the tubercle bacillus. However, all tests were negative for tuberculosis, and the lungs contained no active disease. Though he suspected an infectious etiology, Whipple offered the name intestinal lipodystrophy to emphasize the striking small intestinal pathology.

Although Whipple had surmised a novel infectious agent in 1907, it took almost a century to isolate the causative microbe. Granules within foamy macrophages of the small intestine were detected on periodic acid‐Schiff (PAS) staining in 1949.2 Similar PAS‐positive granules were soon discovered in other tissues and fluid, providing a plausible explanation for the systemic features of the disease.3 Electron microscopy confirmed the presence of infectious bacilli in 1961,4 ushering in the era of antimicrobial treatment for this disease. More recently, using polymerase chain reaction (PCR), a unique bacterial 16S ribosomal RNA gene was isolated in patients with Whipple's disease.5, 6 Phylogenetically classified with the actinobacteria, Tropheryma whipplei (fom the Greek trophe, nourishment, and eryma, barrier) was ultimately subcultured in 2000,7 and immunodetection testing became possible. Using this technique, the archived pathology specimens from the 1907 index case demonstrated numerous intracellular bacteria in the lamina propria, closing the loop started by Whipple nearly a century earlier.8

Whipple's index case report described most of the manifestations of the disease we are familiar with today. As in the original description, arthralgias are the most common initial symptom and may precede diagnosis by a mean of 8 years. Other cardinal features include weight loss, abdominal pain and steatorrhea due to small intestinal involvement. Table 1 summarizes the important signs and symptoms of Whipple's disease.9, 10 One notable manifestation missing in Whipple's report is central nervous system involvement. Central nervous system (CNS) disease ranges from cognitive deficits to encephalitis and focal defects, and may occur years after treatment and without concomitant intestinal symptoms.

A remaining mystery is why this pathogen results only rarely in clinical disease. Caucasians comprise the majority of infected patients, and men are affected 8 times more often than women. An overrepresentation of HLA‐B27 suggests a genetic predisposition, though its role in pathogenesis is unclear. T. whipplei has been identified by PCR methods in asymptomatic individuals, implying additional abnormalities must be present in susceptible hosts for symptoms to occur following colonization.11 The exact immune defects are speculative, and immunodeficiency states (such as HIV) have not been consistently identified in patients with Whipple's disease.

The cornerstone of diagnosing Whipple's disease is upper endoscopy with duodenal biopsy. Flattening of the villi and markedly increased PAS‐positive staining of lamina propria macrophages are strongly suggestive of the diagnosis. PAS‐positive staining is not unique to T. whipplei, however. In patients with profound immunodeficiency, Mycobacterium avium intracellulare may stain positive with PAS. Since Whipple's disease is only rarely associated with HIV, a negative HIV test would favor a diagnosis of Whipple's disease. Electron microscopy may distinguish T. whipplei from its mimickers by morphology. For extraintestinal disease, PCR testing on samples from infected tissue has been found to be a reliable diagnostic aid.9

Given the rarity of the disease, controlled clinical trials addressing optimal treatment are lacking. Current recommendations include initial therapy for 14 days with an agent that crosses the blood‐brain barrier (eg, ceftriaxone) to reduce the incidence of CNS disease. This is then followed by a year or more of oral antimicrobial therapy with trimethoprim‐sulfamethoxazole or a tetracycline.9 While most patients respond within 2 to 3 weeks, relapse may occur in as many as one‐third of patients.

Historical case reports reinforce the case‐based learning paradigm. As the discussant remarks, observation was all too often the only recourse for physicians a century ago. In recounting the 7‐year progression of disease in 1 individual, Whipple provides a unique window into the natural evolution of the key features of this systemic disease. Viewed through the prism of Whipple's eyes, we can recall the striking lymphoid hyperplasia and unusual organisms in the small intestine, cementing our understanding of the pathogenesis of this disorder. Revisiting past cases allows us to learn of and learn from the past.

A 36 year‐old male physician was admitted to a Baltimore hospital in April 1907 with weight loss, weakness, arthralgias, and abdominal distension that had progressed over 5 years.

In 1907, major causes of unexplained weight loss included tuberculosis, hyperthyroidism, cancer, and diabetes. Arthralgias and weakness are not specific. The insidious progression over 5 years narrows the infectious possibilities; tuberculosis and syphilis are important considerations. Since surgical removal was the main treatment for malignancy in 1907, a history of prior surgery might point to a previously diagnosed malignancy that is now progressing.

Five years earlier, while visiting Turkey as a medical missionary, he first noted the onset of arthralgias that lasted 6 to 8 hours and occurred 3 to 4 times per week. Over time, these attacks lasted up to 24 hours and became associated with warmth, swelling, and tenderness of both small and large joints. He gradually lost weight and strength. One year prior to arrival in the hospital, he developed a cough productive of yellow sputum. Seven months prior, he returned from Turkey to Atlanta and noticed an increase in his cough, along with fevers of 100 Fahrenheit and night sweats.

The primacy of the arthralgias in this illness lead me to consider primary rheumatic diseases, and multisystem diseases (including infections) with a predominant skeletal component. In 1907, tests for lupus and the rheumatoid factor were not available. Neither skeletal remains nor works of art provide evidence that rheumatoid arthritis existed until the 19th century, whereas ankylosing spondylitis, gout, and rickets were present by then.

As a medical missionary, he might have acquired a disease endemic to the areas he visited, or the travel history may be a red herring. Familial Mediterranean fever, though prevalent in Turkey and a cause of arthralgias accompanied by recurrent attacks of abdominal pain and fever, is not an acquired disease. Behcet's disease, also known as Silk Trader's Route disease, is found in descendents of the countries that comprised the ancient Silk Route from Japan to the Middle East and may cause arthritis along with oral ulcers, genital lesions, pathergy or uveitis. I would inquire about his ancestry and fevers before dismissing these possibilities.

Although 5 years would be unusually long for tuberculosis to go unrecognized, a physician in the first half of the 20th century would place tuberculosis near the top of possible diagnoses. In 1930, a time when the population of the United States was considerably less, there were over 300,000 cases of tuberculosis. Physicians, and in particular pathologists since autopsies were more commonly performed, often died from tuberculosis since streptomycin, the first antituberculous medication, did not arrive until 1944. At the turn of the 20th century, the ability to detect tubercle bacilli was quite good. Thus, I would include tuberculous peritonitis as a cause of the progressive abdominal symptoms in this physician. In approximately one‐third of patients with tuberculous peritonitis there is evidence of pulmonary disease, and I would try to culture tuberculosis in samples of sputum, a test then so common it probably rivaled our frequent complete blood counts in popularity.

Six months prior, examinations of sputum were negative for tubercle bacilli. Four months prior to arrival, the patient moved to New Mexico. His cough improved but he continued to lose weight and had diarrhea consisting of 3 to 4 loose or semiformed bowel movements per day. Three months prior to admission, he noted an increase in abdominal girth along with right lower quadrant fullness. One month prior, he noted painful swelling and warmth in both ankles as well as dyspnea with exertion.

The increased abdominal girth in the context of chronic illness might be due to ascites, adenopathy, visceromegaly, or mass lesions such as a neoplasm or abscess. If ascites is the cause, one would need to consider primary hepatic disorders, as well as extrahepatic diseases that could progress over years. Infection with hepatitis A virus does not cause chronic liver disease. Hepatitis B, in those days, was referred to as serum hepatitis, and a serum marker for the B virusthe Australia antigenwas not identified until 1967. Cardiac causes of ascites include congestive heart failure and constrictive pericarditis, the latter an important consideration because it is potentially curable. Also, constrictive pericarditis can present as an indolent weight‐losing disease because of chronic visceral congestion. Other considerations include nephrotic syndrome, infection, and neoplasm, including mesothelioma.

Abdominal distention might also be seen with a smoldering abscess. In addition to an appendiceal process, the travel and right lower quadrant localization reminds us to consider ameboma. This patient surely was in an area where amebiasis was endemic, and amebomaa chronic inflammatory form of infection with E. histolytica not associated with diarrhea or liver cystsmay mimic cecal carcinoma. Exertional dyspnea suggests at least the possibility of cardiac disease. Despite the negative sputum cultures, tuberculosis remains high on the list as a cause of constrictive pericarditis or peritonitis, either of which may occur in the absence of active pulmonary disease.

Past medical history included measles and whooping cough as a child, mild pleurisy at age 14, mild influenza 7 years previously. The patient had a tonsillectomy as a child and had a portion of his inferior turbinate bone removed in an attempt to relieve a nasal condition.

On physical exam, the patient was thin and the skin over his face and hands was deep brown. His temperature was 101.5 Fahrenheit, the heart rate was 100, and the respiratory rate was 24. Small lymph nodes were palpable in the axillary and epitrochlear areas. His thorax moved asymmetrically, with less movement on the left apex and slight dullness to percussion in that area. The pulmonic component of the second heart sound was mildly accentuated. The abdomen displayed fullness and tympany, most pronounced in the right lower quadrant without hepatosplenomegaly. The left ankle was swollen, and the overlying skin was tense, shiny, and hot. On both lower legs, areas of discoloration and slight induration were observed, felt to be consistent with faded erythema nodosum.

Though pleurisy has numerous causes, its presence raises the specter of tuberculosis again. The nasal condition triggers thoughts of Wegener's granulomatosis or lethal midline granuloma, both unlikely diagnoses here. The pulmonary exam suggests an apical process, such as tuberculosis, and the accentuated pulmonic heart sound implies pulmonary hypertension, which could be due to a number of chronic pulmonary diseases. The epitrochlear nodes are of interest since lymphoma and Hodgkin's disease rarely involve this area; syphilis and human immunodeficiency virus (HIV) are a few of the chronic diseases that may involve this lymph node region. More helpful is the absence of hepatosplenomegaly, since many indolent malignancies and infections would be expected to enlarge these organs by this point.

Monoarticular arthritis is often due to infection, and less likely due to rheumatoid disease. When rheumatoid arthritis flares, the entire skeleton flares, not single joints. Given the indolence and this single joint involvement, tuberculosis again comes to mind.

I would next want to obtain a plain chest radiograph, looking for evidence of tuberculosis. As with any test, one should ask how this will change management. In 1907, antituberculous medications were not available, so therapy was directed at lowering oxygen tension in the primary site of infection; for example, pulmonary disease was addressed via pneumothorax. If the chest radiograph provides little hint of tuberculosis, then consideration must be given to exploratory surgery of the abdomen given the focal abnormality in the right lower quadrant.

A peripheral blood smear revealed a hypochromic microcytic anemia. The total red blood cell count was 4.468 million/mm³ (normal range for men is 4.52‐5.90 million/mm³), white blood cell count was 8180/mm³, including 80% granulocytes and 9% eosinophils. On gross inspection, the stool was clay‐colored, and stool microscopy demonstrated large numbers of neutral fat droplets, but no ova, parasites, or tubercle bacilli. Urinalysis revealed no albumin or casts, and the bones were normal on ankle radiographs. Another sample of sputum revealed no tubercle bacilli, and intradermal placement of tuberculin provoked no reaction.

His negative tuberculin skin reaction is unusual for that era, because of the prevalence of tuberculosis. Most likely, he is anergic because of his severe underlying illness, and the absent reaction is thus not all that helpful a clue. Multiple negative sputum examinations lower the possibility of pulmonary, but not extrapulmonary, tuberculosis. The absence of bony destruction on ankle radiographs lowers my suspicion for tuberculous arthritis.

The excess stool fat implies steatogenic diarrhea from malabsorption, and 2 categories here are pancreatic and luminal diseases. Of these 2, pancreatic etiologies produce more severe malabsorption. We do not hear mention of jaundice, however, and I cannot see how to link the pancreas to the arthritis. A chronic infection which may produce malabsorption and eosinophilia is strongyloidiasis, endemic in the southeastern United States. However, this patient did not manifest the most common finding of chronic strongyloidiasis, namely asthma. Adrenal insufficiency, as might result from disseminated tuberculosis, is associated with increased skin pigmentation, diarrhea, and eosinophilia. However, the diarrhea of adrenal insufficiency is not malabsorptive, and serum electrolytes and cortisol tests were not available then to confirm this diagnosis antemortem.

In an attempt to identify a unifying cause of chronic arthritis, malabsorption, and increased skin pigmentation, I must consider Whipple's disease first and foremost. Physicians then were strapped and observation was often the default mode of the day. Given the abdominal findings, an exploratory laparotomy would be warranted if his condition deteriorated.

Despite forced oral feedings, the patient continued to lose weight, from his normal of 175 pounds to a nadir of 145 pounds. Because of worsening abdominal distention, the patient underwent exploratory abdominal surgery on the twenty‐first hospital day. Intraoperatively, no ascites was seen, but his mesenteric lymph nodes were hard and markedly enlarged. The abdomen was closed without further intervention. Two days after the surgery, the patient abruptly developed dyspnea. His respirations were 40 per minute, heart rate was 120, and he had minimal rales at the lung bases without findings of consolidation. He died 2 hours later, on the twenty‐third hospital day, and an autopsy was performed.

The final event may have been a pulmonary embolism. As for the adenopathy, lymphoma and tuberculosis are possible. Heavy chain disease, an unusual lymphoproliferative disorder found in persons from the old Silk Trader's Route from the Middle East to the Orient, is a remote prospect. However, 5 years is just too indolent for most cancers and would be very unusual for tuberculosis. I think the findings support Whipple's disease, and I wonder if this was the first reported case.

On postmortem examination, the abdominal adenopathy was striking. The small intestine contained enlarged villi with thickened submucosa, and the mesenteric nodes were enlarged with fat deposits and abnormal foamy cells. Within these foamy cells, microscopy revealed numerous rod‐shaped organisms. All studies were negative for tuberculosis, and although the pathologist, Dr. George Hoyt Whipple, suspected an infectious etiology, he offered the name intestinal lipodystrophy to emphasize the striking small intestinal changes he witnessed at autopsy, and which are the hallmarks of the disease that now bears his name. Whipple also shared the 1934 Nobel Prize in Physiology or Medicine with Minot and Murphy for their discovery that a nutritional substance in liver, now known as vitamin B12, was beneficial in treating pernicious anemia.

COMMENTARY

This is the index case of Whipple's disease, summarized from the original 1907 description.1 George Hoyt Whipple, then a pathologist at Johns Hopkins, highlights the value of keen observation and a well‐done case report in describing a new disease entity. One of the roles of case reports is to detail the features of an unknown disease. In this capacity, Whipple's summary is exemplary. His achievement was having the openness of mind to realize he was witnessing something novel, and to take the first step on the road to discovery. Although Whipple suspected he was staring at a unique disease, he could not pinpoint the culprit bacteria and he had trouble squaring the extraintestinal findings with the marked intestinal anomalies. It was left to decades of input from others to confirm the association of arthralgias, eosinophilia, skin hyperpigmentation, and cardiac valve abnormalities with intestinal malabsorption, and to culture the infectious agent.

In his discussion, Whipple recognized he was confronted with a novel clinical entity. Prior to surgery, pulmonary and mesenteric tuberculosis were suspected, based on the fevers, weight loss, cough, fat malabsorption, and lymphadenopathy. However, he felt the left apical exam was more representative of retraction from prior disease than active infection. He was also bothered by the negative skin reaction and sputum tests. At surgery, the pronounced adenopathy suggested sarcoma or Hodgkin's disease but postmortem examination eliminated these possibilities. At autopsy, the abdominal findings were most striking. The small intestine demonstrated enlarged villi with thickened submucosa and markedly enlarged mesenteric lymph glands containing large fat deposits and distinctly abnormal foamy cells. These foamy macrophages contained great numbers of rod‐shaped organisms resembling the tubercle bacillus. However, all tests were negative for tuberculosis, and the lungs contained no active disease. Though he suspected an infectious etiology, Whipple offered the name intestinal lipodystrophy to emphasize the striking small intestinal pathology.

Although Whipple had surmised a novel infectious agent in 1907, it took almost a century to isolate the causative microbe. Granules within foamy macrophages of the small intestine were detected on periodic acid‐Schiff (PAS) staining in 1949.2 Similar PAS‐positive granules were soon discovered in other tissues and fluid, providing a plausible explanation for the systemic features of the disease.3 Electron microscopy confirmed the presence of infectious bacilli in 1961,4 ushering in the era of antimicrobial treatment for this disease. More recently, using polymerase chain reaction (PCR), a unique bacterial 16S ribosomal RNA gene was isolated in patients with Whipple's disease.5, 6 Phylogenetically classified with the actinobacteria, Tropheryma whipplei (fom the Greek trophe, nourishment, and eryma, barrier) was ultimately subcultured in 2000,7 and immunodetection testing became possible. Using this technique, the archived pathology specimens from the 1907 index case demonstrated numerous intracellular bacteria in the lamina propria, closing the loop started by Whipple nearly a century earlier.8

Whipple's index case report described most of the manifestations of the disease we are familiar with today. As in the original description, arthralgias are the most common initial symptom and may precede diagnosis by a mean of 8 years. Other cardinal features include weight loss, abdominal pain and steatorrhea due to small intestinal involvement. Table 1 summarizes the important signs and symptoms of Whipple's disease.9, 10 One notable manifestation missing in Whipple's report is central nervous system involvement. Central nervous system (CNS) disease ranges from cognitive deficits to encephalitis and focal defects, and may occur years after treatment and without concomitant intestinal symptoms.

A remaining mystery is why this pathogen results only rarely in clinical disease. Caucasians comprise the majority of infected patients, and men are affected 8 times more often than women. An overrepresentation of HLA‐B27 suggests a genetic predisposition, though its role in pathogenesis is unclear. T. whipplei has been identified by PCR methods in asymptomatic individuals, implying additional abnormalities must be present in susceptible hosts for symptoms to occur following colonization.11 The exact immune defects are speculative, and immunodeficiency states (such as HIV) have not been consistently identified in patients with Whipple's disease.

The cornerstone of diagnosing Whipple's disease is upper endoscopy with duodenal biopsy. Flattening of the villi and markedly increased PAS‐positive staining of lamina propria macrophages are strongly suggestive of the diagnosis. PAS‐positive staining is not unique to T. whipplei, however. In patients with profound immunodeficiency, Mycobacterium avium intracellulare may stain positive with PAS. Since Whipple's disease is only rarely associated with HIV, a negative HIV test would favor a diagnosis of Whipple's disease. Electron microscopy may distinguish T. whipplei from its mimickers by morphology. For extraintestinal disease, PCR testing on samples from infected tissue has been found to be a reliable diagnostic aid.9

Given the rarity of the disease, controlled clinical trials addressing optimal treatment are lacking. Current recommendations include initial therapy for 14 days with an agent that crosses the blood‐brain barrier (eg, ceftriaxone) to reduce the incidence of CNS disease. This is then followed by a year or more of oral antimicrobial therapy with trimethoprim‐sulfamethoxazole or a tetracycline.9 While most patients respond within 2 to 3 weeks, relapse may occur in as many as one‐third of patients.

Historical case reports reinforce the case‐based learning paradigm. As the discussant remarks, observation was all too often the only recourse for physicians a century ago. In recounting the 7‐year progression of disease in 1 individual, Whipple provides a unique window into the natural evolution of the key features of this systemic disease. Viewed through the prism of Whipple's eyes, we can recall the striking lymphoid hyperplasia and unusual organisms in the small intestine, cementing our understanding of the pathogenesis of this disorder. Revisiting past cases allows us to learn of and learn from the past.

A 36 year‐old male physician was admitted to a Baltimore hospital in April 1907 with weight loss, weakness, arthralgias, and abdominal distension that had progressed over 5 years.

In 1907, major causes of unexplained weight loss included tuberculosis, hyperthyroidism, cancer, and diabetes. Arthralgias and weakness are not specific. The insidious progression over 5 years narrows the infectious possibilities; tuberculosis and syphilis are important considerations. Since surgical removal was the main treatment for malignancy in 1907, a history of prior surgery might point to a previously diagnosed malignancy that is now progressing.

Five years earlier, while visiting Turkey as a medical missionary, he first noted the onset of arthralgias that lasted 6 to 8 hours and occurred 3 to 4 times per week. Over time, these attacks lasted up to 24 hours and became associated with warmth, swelling, and tenderness of both small and large joints. He gradually lost weight and strength. One year prior to arrival in the hospital, he developed a cough productive of yellow sputum. Seven months prior, he returned from Turkey to Atlanta and noticed an increase in his cough, along with fevers of 100 Fahrenheit and night sweats.

The primacy of the arthralgias in this illness lead me to consider primary rheumatic diseases, and multisystem diseases (including infections) with a predominant skeletal component. In 1907, tests for lupus and the rheumatoid factor were not available. Neither skeletal remains nor works of art provide evidence that rheumatoid arthritis existed until the 19th century, whereas ankylosing spondylitis, gout, and rickets were present by then.

As a medical missionary, he might have acquired a disease endemic to the areas he visited, or the travel history may be a red herring. Familial Mediterranean fever, though prevalent in Turkey and a cause of arthralgias accompanied by recurrent attacks of abdominal pain and fever, is not an acquired disease. Behcet's disease, also known as Silk Trader's Route disease, is found in descendents of the countries that comprised the ancient Silk Route from Japan to the Middle East and may cause arthritis along with oral ulcers, genital lesions, pathergy or uveitis. I would inquire about his ancestry and fevers before dismissing these possibilities.

Although 5 years would be unusually long for tuberculosis to go unrecognized, a physician in the first half of the 20th century would place tuberculosis near the top of possible diagnoses. In 1930, a time when the population of the United States was considerably less, there were over 300,000 cases of tuberculosis. Physicians, and in particular pathologists since autopsies were more commonly performed, often died from tuberculosis since streptomycin, the first antituberculous medication, did not arrive until 1944. At the turn of the 20th century, the ability to detect tubercle bacilli was quite good. Thus, I would include tuberculous peritonitis as a cause of the progressive abdominal symptoms in this physician. In approximately one‐third of patients with tuberculous peritonitis there is evidence of pulmonary disease, and I would try to culture tuberculosis in samples of sputum, a test then so common it probably rivaled our frequent complete blood counts in popularity.

Six months prior, examinations of sputum were negative for tubercle bacilli. Four months prior to arrival, the patient moved to New Mexico. His cough improved but he continued to lose weight and had diarrhea consisting of 3 to 4 loose or semiformed bowel movements per day. Three months prior to admission, he noted an increase in abdominal girth along with right lower quadrant fullness. One month prior, he noted painful swelling and warmth in both ankles as well as dyspnea with exertion.

The increased abdominal girth in the context of chronic illness might be due to ascites, adenopathy, visceromegaly, or mass lesions such as a neoplasm or abscess. If ascites is the cause, one would need to consider primary hepatic disorders, as well as extrahepatic diseases that could progress over years. Infection with hepatitis A virus does not cause chronic liver disease. Hepatitis B, in those days, was referred to as serum hepatitis, and a serum marker for the B virusthe Australia antigenwas not identified until 1967. Cardiac causes of ascites include congestive heart failure and constrictive pericarditis, the latter an important consideration because it is potentially curable. Also, constrictive pericarditis can present as an indolent weight‐losing disease because of chronic visceral congestion. Other considerations include nephrotic syndrome, infection, and neoplasm, including mesothelioma.

Abdominal distention might also be seen with a smoldering abscess. In addition to an appendiceal process, the travel and right lower quadrant localization reminds us to consider ameboma. This patient surely was in an area where amebiasis was endemic, and amebomaa chronic inflammatory form of infection with E. histolytica not associated with diarrhea or liver cystsmay mimic cecal carcinoma. Exertional dyspnea suggests at least the possibility of cardiac disease. Despite the negative sputum cultures, tuberculosis remains high on the list as a cause of constrictive pericarditis or peritonitis, either of which may occur in the absence of active pulmonary disease.

Past medical history included measles and whooping cough as a child, mild pleurisy at age 14, mild influenza 7 years previously. The patient had a tonsillectomy as a child and had a portion of his inferior turbinate bone removed in an attempt to relieve a nasal condition.

On physical exam, the patient was thin and the skin over his face and hands was deep brown. His temperature was 101.5 Fahrenheit, the heart rate was 100, and the respiratory rate was 24. Small lymph nodes were palpable in the axillary and epitrochlear areas. His thorax moved asymmetrically, with less movement on the left apex and slight dullness to percussion in that area. The pulmonic component of the second heart sound was mildly accentuated. The abdomen displayed fullness and tympany, most pronounced in the right lower quadrant without hepatosplenomegaly. The left ankle was swollen, and the overlying skin was tense, shiny, and hot. On both lower legs, areas of discoloration and slight induration were observed, felt to be consistent with faded erythema nodosum.

Though pleurisy has numerous causes, its presence raises the specter of tuberculosis again. The nasal condition triggers thoughts of Wegener's granulomatosis or lethal midline granuloma, both unlikely diagnoses here. The pulmonary exam suggests an apical process, such as tuberculosis, and the accentuated pulmonic heart sound implies pulmonary hypertension, which could be due to a number of chronic pulmonary diseases. The epitrochlear nodes are of interest since lymphoma and Hodgkin's disease rarely involve this area; syphilis and human immunodeficiency virus (HIV) are a few of the chronic diseases that may involve this lymph node region. More helpful is the absence of hepatosplenomegaly, since many indolent malignancies and infections would be expected to enlarge these organs by this point.

Monoarticular arthritis is often due to infection, and less likely due to rheumatoid disease. When rheumatoid arthritis flares, the entire skeleton flares, not single joints. Given the indolence and this single joint involvement, tuberculosis again comes to mind.

I would next want to obtain a plain chest radiograph, looking for evidence of tuberculosis. As with any test, one should ask how this will change management. In 1907, antituberculous medications were not available, so therapy was directed at lowering oxygen tension in the primary site of infection; for example, pulmonary disease was addressed via pneumothorax. If the chest radiograph provides little hint of tuberculosis, then consideration must be given to exploratory surgery of the abdomen given the focal abnormality in the right lower quadrant.

A peripheral blood smear revealed a hypochromic microcytic anemia. The total red blood cell count was 4.468 million/mm³ (normal range for men is 4.52‐5.90 million/mm³), white blood cell count was 8180/mm³, including 80% granulocytes and 9% eosinophils. On gross inspection, the stool was clay‐colored, and stool microscopy demonstrated large numbers of neutral fat droplets, but no ova, parasites, or tubercle bacilli. Urinalysis revealed no albumin or casts, and the bones were normal on ankle radiographs. Another sample of sputum revealed no tubercle bacilli, and intradermal placement of tuberculin provoked no reaction.

His negative tuberculin skin reaction is unusual for that era, because of the prevalence of tuberculosis. Most likely, he is anergic because of his severe underlying illness, and the absent reaction is thus not all that helpful a clue. Multiple negative sputum examinations lower the possibility of pulmonary, but not extrapulmonary, tuberculosis. The absence of bony destruction on ankle radiographs lowers my suspicion for tuberculous arthritis.

The excess stool fat implies steatogenic diarrhea from malabsorption, and 2 categories here are pancreatic and luminal diseases. Of these 2, pancreatic etiologies produce more severe malabsorption. We do not hear mention of jaundice, however, and I cannot see how to link the pancreas to the arthritis. A chronic infection which may produce malabsorption and eosinophilia is strongyloidiasis, endemic in the southeastern United States. However, this patient did not manifest the most common finding of chronic strongyloidiasis, namely asthma. Adrenal insufficiency, as might result from disseminated tuberculosis, is associated with increased skin pigmentation, diarrhea, and eosinophilia. However, the diarrhea of adrenal insufficiency is not malabsorptive, and serum electrolytes and cortisol tests were not available then to confirm this diagnosis antemortem.

In an attempt to identify a unifying cause of chronic arthritis, malabsorption, and increased skin pigmentation, I must consider Whipple's disease first and foremost. Physicians then were strapped and observation was often the default mode of the day. Given the abdominal findings, an exploratory laparotomy would be warranted if his condition deteriorated.

Despite forced oral feedings, the patient continued to lose weight, from his normal of 175 pounds to a nadir of 145 pounds. Because of worsening abdominal distention, the patient underwent exploratory abdominal surgery on the twenty‐first hospital day. Intraoperatively, no ascites was seen, but his mesenteric lymph nodes were hard and markedly enlarged. The abdomen was closed without further intervention. Two days after the surgery, the patient abruptly developed dyspnea. His respirations were 40 per minute, heart rate was 120, and he had minimal rales at the lung bases without findings of consolidation. He died 2 hours later, on the twenty‐third hospital day, and an autopsy was performed.

The final event may have been a pulmonary embolism. As for the adenopathy, lymphoma and tuberculosis are possible. Heavy chain disease, an unusual lymphoproliferative disorder found in persons from the old Silk Trader's Route from the Middle East to the Orient, is a remote prospect. However, 5 years is just too indolent for most cancers and would be very unusual for tuberculosis. I think the findings support Whipple's disease, and I wonder if this was the first reported case.

On postmortem examination, the abdominal adenopathy was striking. The small intestine contained enlarged villi with thickened submucosa, and the mesenteric nodes were enlarged with fat deposits and abnormal foamy cells. Within these foamy cells, microscopy revealed numerous rod‐shaped organisms. All studies were negative for tuberculosis, and although the pathologist, Dr. George Hoyt Whipple, suspected an infectious etiology, he offered the name intestinal lipodystrophy to emphasize the striking small intestinal changes he witnessed at autopsy, and which are the hallmarks of the disease that now bears his name. Whipple also shared the 1934 Nobel Prize in Physiology or Medicine with Minot and Murphy for their discovery that a nutritional substance in liver, now known as vitamin B12, was beneficial in treating pernicious anemia.

COMMENTARY

This is the index case of Whipple's disease, summarized from the original 1907 description.1 George Hoyt Whipple, then a pathologist at Johns Hopkins, highlights the value of keen observation and a well‐done case report in describing a new disease entity. One of the roles of case reports is to detail the features of an unknown disease. In this capacity, Whipple's summary is exemplary. His achievement was having the openness of mind to realize he was witnessing something novel, and to take the first step on the road to discovery. Although Whipple suspected he was staring at a unique disease, he could not pinpoint the culprit bacteria and he had trouble squaring the extraintestinal findings with the marked intestinal anomalies. It was left to decades of input from others to confirm the association of arthralgias, eosinophilia, skin hyperpigmentation, and cardiac valve abnormalities with intestinal malabsorption, and to culture the infectious agent.

In his discussion, Whipple recognized he was confronted with a novel clinical entity. Prior to surgery, pulmonary and mesenteric tuberculosis were suspected, based on the fevers, weight loss, cough, fat malabsorption, and lymphadenopathy. However, he felt the left apical exam was more representative of retraction from prior disease than active infection. He was also bothered by the negative skin reaction and sputum tests. At surgery, the pronounced adenopathy suggested sarcoma or Hodgkin's disease but postmortem examination eliminated these possibilities. At autopsy, the abdominal findings were most striking. The small intestine demonstrated enlarged villi with thickened submucosa and markedly enlarged mesenteric lymph glands containing large fat deposits and distinctly abnormal foamy cells. These foamy macrophages contained great numbers of rod‐shaped organisms resembling the tubercle bacillus. However, all tests were negative for tuberculosis, and the lungs contained no active disease. Though he suspected an infectious etiology, Whipple offered the name intestinal lipodystrophy to emphasize the striking small intestinal pathology.

Although Whipple had surmised a novel infectious agent in 1907, it took almost a century to isolate the causative microbe. Granules within foamy macrophages of the small intestine were detected on periodic acid‐Schiff (PAS) staining in 1949.2 Similar PAS‐positive granules were soon discovered in other tissues and fluid, providing a plausible explanation for the systemic features of the disease.3 Electron microscopy confirmed the presence of infectious bacilli in 1961,4 ushering in the era of antimicrobial treatment for this disease. More recently, using polymerase chain reaction (PCR), a unique bacterial 16S ribosomal RNA gene was isolated in patients with Whipple's disease.5, 6 Phylogenetically classified with the actinobacteria, Tropheryma whipplei (fom the Greek trophe, nourishment, and eryma, barrier) was ultimately subcultured in 2000,7 and immunodetection testing became possible. Using this technique, the archived pathology specimens from the 1907 index case demonstrated numerous intracellular bacteria in the lamina propria, closing the loop started by Whipple nearly a century earlier.8

Whipple's index case report described most of the manifestations of the disease we are familiar with today. As in the original description, arthralgias are the most common initial symptom and may precede diagnosis by a mean of 8 years. Other cardinal features include weight loss, abdominal pain and steatorrhea due to small intestinal involvement. Table 1 summarizes the important signs and symptoms of Whipple's disease.9, 10 One notable manifestation missing in Whipple's report is central nervous system involvement. Central nervous system (CNS) disease ranges from cognitive deficits to encephalitis and focal defects, and may occur years after treatment and without concomitant intestinal symptoms.

A remaining mystery is why this pathogen results only rarely in clinical disease. Caucasians comprise the majority of infected patients, and men are affected 8 times more often than women. An overrepresentation of HLA‐B27 suggests a genetic predisposition, though its role in pathogenesis is unclear. T. whipplei has been identified by PCR methods in asymptomatic individuals, implying additional abnormalities must be present in susceptible hosts for symptoms to occur following colonization.11 The exact immune defects are speculative, and immunodeficiency states (such as HIV) have not been consistently identified in patients with Whipple's disease.

The cornerstone of diagnosing Whipple's disease is upper endoscopy with duodenal biopsy. Flattening of the villi and markedly increased PAS‐positive staining of lamina propria macrophages are strongly suggestive of the diagnosis. PAS‐positive staining is not unique to T. whipplei, however. In patients with profound immunodeficiency, Mycobacterium avium intracellulare may stain positive with PAS. Since Whipple's disease is only rarely associated with HIV, a negative HIV test would favor a diagnosis of Whipple's disease. Electron microscopy may distinguish T. whipplei from its mimickers by morphology. For extraintestinal disease, PCR testing on samples from infected tissue has been found to be a reliable diagnostic aid.9

Given the rarity of the disease, controlled clinical trials addressing optimal treatment are lacking. Current recommendations include initial therapy for 14 days with an agent that crosses the blood‐brain barrier (eg, ceftriaxone) to reduce the incidence of CNS disease. This is then followed by a year or more of oral antimicrobial therapy with trimethoprim‐sulfamethoxazole or a tetracycline.9 While most patients respond within 2 to 3 weeks, relapse may occur in as many as one‐third of patients.

Historical case reports reinforce the case‐based learning paradigm. As the discussant remarks, observation was all too often the only recourse for physicians a century ago. In recounting the 7‐year progression of disease in 1 individual, Whipple provides a unique window into the natural evolution of the key features of this systemic disease. Viewed through the prism of Whipple's eyes, we can recall the striking lymphoid hyperplasia and unusual organisms in the small intestine, cementing our understanding of the pathogenesis of this disorder. Revisiting past cases allows us to learn of and learn from the past.

A30‐year‐old woman was referred for evaluation of chest pain, palpitations, and exercise intolerance. She had been previously healthy, active, and physically fit. Five months prior to our evaluation, she had an elective C5C6 cervical spine discectomy with interbody allograft fusion for a chronic neck injury that occurred 11 years ago during gymnastics. Two weeks after spine surgery, the patient developed numbness and tingling of her left thumb and palm that occurred with exertion or exposure to cold and subsided with rest. These episodes increased in frequency and intensity and after 1 week became associated with sharp, occasionally stabbing chest pain that radiated to the left arm. On one occasion, the patient had an episode of exertional chest pain with prolonged left arm cyanosis. Emergent left upper extremity angiography revealed normal great vessel anatomy with spasm of the radial artery and collateral ulnar flow. The patient was diagnosed with Raynaud's phenomenon and was started on nifedipine. A subsequent rheumatologic evaluation was unrevealing, and the patient was empirically switched to amlodipine with no improvement in symptoms.

This otherwise very healthy 30‐year‐old developed a multitude of symptoms. The patient's chest pain is atypical and in a young woman is unlikely to signify atherosclerotic coronary disease, but it should not be entirely disregarded. Vasospasm triggered by exposure to cold does raise suspicion for Raynaud's phenomenon, which is not uncommon in this demographic. However, this presentation is quite unusual because the vasospasm was limited to one vascular distribution of one extremity. Associated coronary vasospasm could explain the other symptoms, although coronary spasm is generally not associated with Raynaud's phenomenon. Vasculitis may also affect the pulmonary vasculature, leading to pulmonary hypertension and exercise intolerance. The temporal association with her spine surgery is intriguing but of unclear significance.

The patient continued to have frequent exertional episodes of sharp precordial chest pain radiating to her left arm that were accompanied by dyspnea and left upper extremity symptoms despite amlodipine therapy. These now occurred with limited activity when she walked 1 to 2 blocks uphill. Over the previous 2 months, she had also noticed palpitations occurring reliably with exercise that were relieved with 15 to 20 min of rest. With prolonged episodes, she reported dizziness, nausea, and blurry vision that improved with lying down. She twice had syncope with these symptoms. She noted lower extremity edema while taking calcium channel blockers, but this had resolved after discontinuation of the drugs.

The patient's past medical history included several high‐school orthopedic injuries. She had 2 kidney stones at ages 18 and 23 and had an appendectomy at age 28. Her only medication was an oral contraceptive, and she had discontinued the amlodipine. She denied the use of tobacco, alcohol, herbal medications, or illicit substances. There was no family history of sudden death or heart disease.

Palpitations in a 30‐year‐old woman may signify a cardiac arrhythmia. Paroxysmal supraventricular arrhythmias, such as atrioventricular nodal reentrant tachycardia, atrial tachycardia, and atrial fibrillation, are well described in the young. Ventricular tachycardia (VT) is another possible cause and could be idiopathic or related to occult structural heart disease. Young patients typically tolerate lone arrhythmias quite well, and her failure to do so raises suspicion for concomitant structural heart disease. Her palpitations may be from appropriate sinus tachycardia, which could be compensatory because of inadequate cardiac output reserve, which in turn could be caused by valvular disease, congenital heart disease, or ventricular dysfunction. The exertional chest pain is worrisome for ischemia. Pulmonary hypertension, severe ventricular hypertrophy, or congenital anomalies of the coronary circulation could lead to subendocardial myocardial ischemia with exertion, resulting in angina, dyspnea, and arrhythmias. However, the patient also experiences exertional palpitations without chest pain, which may signify an exertional tachyarrhythmia possibly mediated by catecholamines. Based solely on the history, the differential diagnosis remains broad.

On physical examination, the patient was a fit, thin, healthy woman. Her blood pressure was 120/70 mm Hg supine in both arms and 115/75 mm Hg standing; her pulse was 85 supine and 110 standing, Oxygen saturation was 100% on room air. A cardiac exam revealed a normal jugular venous pressure, normal point of maximal impulse, regular rhythm with occasional ectopy, normal S1, and physiologically split S2 without extra heart sounds or murmurs. The right ventricular impulse was faintly palpable at the left sternal border. Head, neck, chest, abdominal, musculoskeletal, neurologic, extremity, and peripheral pulse examinations were normal.

Laboratory data showed a normal complete blood count and normal chemistries. Serum tests for hepatitis C antibody, cardiolipin antibody, rheumatoid factor, cryoglobulins, and anti‐nuclear antibody were negative. The erythrocyte sedimentation rate and thyroid stimulating hormone levels were within normal limits. An electrocardiogram (ECG) demonstrated a normal sinus rhythm with frequent premature ventricular complexes (PVCs) and normal axis and intervals. (Figure 1). The PR segment was normal and without preexcitation. A prior ECG from 3 months ago was similar with ventricular trigeminy.

Figure 1

Her unremarkable cardiac examination does not favor structural or valvular heart disease, and there are no obvious stigmata of vasculitis. She did become mildly tachycardic upon standing, and this raises the possibility of orthostatic tachycardia. A comprehensive rheumatologic panel revealed no evidence of autoimmune disease or vasculitis, and the clinical constellation is not consistent with primary or secondary Raynaud's disease. The ECG demonstrates frequent monomorphic PVCs complexes with a left bundle branch block pattern and an inferior axis. This pattern suggests that the PVCs arise from the right ventricular outflow tract. Idiopathic right ventricular outflow tract VT and arrhythmogenic right ventricular dysplasia must be considered as a cause of exertional or catecholamine‐mediated tachycardia. The normal ECG argues against arrhythmogenic right ventricular dysplasia, in which patients typically have incomplete or complete right bundle branch block, right precordial T wave abnormalities, and occasionally epsilon waves. Her QT interval is normal, but excluding long‐QT syndrome with a single ECG has poor sensitivity. The next critical step is to document her cardiac rhythm during symptoms and to exclude malignant arrhythmias.

An event recorder and exercise echocardiogram were ordered. While the patient was wearing her event recorder, she had 4 episodes of exertional syncope while hiking and successfully triggered event recording before losing consciousness. She had chest pain and left arm pain after regaining consciousness. The patient came to the emergency room for evaluation. Her blood pressure was 116/80 mm Hg supine and 112/70 mm Hg seated. Her heart rate increased from 82 supine to 132 seated. The physical examination was unremarkable. ECG showed sinus rhythm with frequent PVCs. Troponin‐I measurements 10 hours apart were 0.7 and 0.3 g/L (normal < 1.1), with normal creatinine kinase and creatinine kinase MB fractions. Interrogation of the event recorder revealed multiple episodes of a narrow complex tachycardia with rates up to 180 bpm that correlated with symptoms (Figure 2). There were no episodes of wide complex tachycardia.

Figure 2

The patient was not hypotensive in the emergency room, but she had evidence of a marked orthostatic tachycardia. The minimal but significant troponin elevations are also troubling. Although her clinical picture is not consistent with an acute coronary syndrome, I am concerned about other mechanisms of myocardial ischemia or injury, such as a coronary anomaly or subendocardial ischemia from globally reduced myocardial perfusion. The presence of event recorder data from her syncopal events was fortuitous and revealed a supraventricular tachycardia. The arrhythmia was gradual in onset and resolution and had no triggers, such as premature atrial or ventricular complexes, which could suggest reentrant arrhythmias. The P wave morphology was also unchanged, and this argues against an atrial tachycardia. These findings are consistent with sinus tachycardia, which was notably out of proportion to her workload. This arrhythmia may be the primary cause of syncope, such as in inappropriate sinus tachycardia, or it may be a compensatory mechanism. Tachycardia from coronary vasospasm is often preceded by ST segment changes, which are not seen here. Although the event recorder had no episodes of VT, the patient's persistent frequent PVCs are still of concern. I would obtain an echocardiogram to exclude structural heart disease and an exercise test to exclude exertional VT. Finally, coronary angiography may be helpful in excluding congenital anomalies.

The patient was admitted for evaluation. An exercise treadmill test was performed, and the patient exercised 20 min on the standard Bruce protocol with a peak heart rate of 180 bpm. The test was notable for a premature rise in heart rate (in stage 1) without a rise in blood pressure. There were no symptoms or ST/T wave changes. Transthoracic echocardiogram showed normal left ventricular size and function with normal anatomy, valves, and hemodynamics. Coronary angiography showed a right dominant system with normal anatomy and no atherosclerotic disease.

Ventricular arrhythmias could not be elicited with exercise. Her high exercise tolerance virtually excluded hemodynamically significant structural or valvular disease, and this was confirmed by the echocardiogram. Coronary angiography excluded coronary anomalies and myocardial bridging. The most intriguing finding is the rise in the patient's heart rate out of proportion to the workload. This, along with her orthostatic tachycardia, raises the issue of inappropriate sinus tachycardia or postural orthostatic tachycardia syndrome (POTS). Carotid hypersensitivity is also a possibility. The patient was hiking when she fainted, and even light pressure on the patient's neck with head turning or from a camera strap, for example, could produce syncope. Although carotid hypersensitivity usually results in sinus bradycardia and AV block, it may be followed by reflex tachycardia, which was seen in this patient's event recordings. I would perform a tilt‐table test with carotid massage to make the diagnosis.

Tilt‐table testing was performed (Figure 3). Her supine blood pressure was 128/68 mm Hg, and her heart rate was 72 bpm with no change during the 10‐min supine period. Upon elevation to a 70‐degree tilt, the patient had an immediate increase in her heart rate to 160 bpm with a blood pressure nadir of 109/58 mm Hg and symptoms of palpitations, dizziness, dyspnea, chest pain, blurry vision, and nausea. Her peak heart rate was 172 bpm, and her peak blood pressure was 122/72 mm Hg. Vital signs did not change in response to carotid sinus massage in the supine or upright positions.

Figure 3

The tilt‐table test has 3 notable findings. First, her heart rate increased rapidly with tilt and decreased rapidly in supine recovery. Second, her usual symptoms started immediately after tilt and quickly resolved in recovery when vital signs returned to baseline. Finally, there was only a modest drop in blood pressure. These findings are classic for POTS. POTS is defined as symptomatic orthostasis with a heart rate increase of 30 bpm or a heart rate of 120 bpm. The physiologic lesions found in the syndrome are heterogeneous, but they all lead to a failure of orthostatic compensation. In POTS, the tachycardia is a reflex secondary to hypotension (baroreceptor reflex) or reduced preload (cardiac mechanoreceptors), in contrast to inappropriate sinus tachycardia. Interestingly, blood pressure is usually preserved until the final moments preceding syncope, when venous return further declines, tachycardia decreases the diastolic filling time and stroke volume, and mean arterial pressure sharply falls.

The patient was started on labetalol (200 mg 3 times daily), and her symptoms worsened. She also developed nausea and constipation. Midodrine and pindolol were also tried without success. She was then switched to fludrocortisone, salt supplementation, and leg support stockings with dramatic improvement.

COMMENTARY

In 1871, DeCosta1 published a report on the irritable heart, noting an affliction of extreme fatigue and exercise intolerance that occurred suddenly and without obvious cause. Subsequently, the terms vasoregulatory asthenia and neurocirculatory asthenia were used to link cardiovascular symptoms to impaired regulation of peripheral blood flow.2, 3 The term POTS was first used in 1982 to describe a single patient with postural tachycardia without hypotension and palpitations, weakness, abdominal pain, and presyncope.4

POTS is one of several disorders of autonomic control associated with orthostatic intolerance. The criteria for diagnosis are listed in Table 1. POTS typically occurs in women between the ages of 15 and 50 but tends to present during adolescence or young adulthood. The physiology has only recently been elucidated. When a person stands, 500 cc of the total blood volume is displaced to the dependent extremities and inferior mesenteric vessels.5 Normally, orthostatic stabilization occurs in less than 1 minute via 3 mechanisms: baroreceptor input, sympathetic reflex tachycardia and vasoconstriction, and enhanced venous return via the pumping action of skeletal muscles and venoconstriction. In POTS, there is a failure of at least one of these mechanisms, leading to decreased venous return, a 40% reduction in stroke volume, and cerebral hypoperfusion.6

POTS is divided into 2 major subtypes on the basis of pathophysiology.5, 7 The partial dysautonomic form is the most common and the type that this patient most likely had. In this form, the development of an acquired peripheral autonomic neuropathy results in a failure of sympathetic venoconstriction, which leads to excessive venous pooling in the lower extremities and splanchnic circulation.8, 9 Failure to mobilize this venous reservoir upon standing leads to excessive orthostatic tachycardia secondary to a marked reduction in stroke volume. Peripheral arterial vasoconstriction is generally preserved, which is why midodrine, an arterial vasoconstrictor, did not improve symptoms. The labetalol may have further exacerbated peripheral pooling because of its alpha‐adrenergic blocking properties. Because total plasma volume is decreased and plasma renin activity is inappropriately low,10 volume expanders, including salt, low‐dose steroids, and fluids, can attenuate symptoms.11 The extrinsic venous compression from leg and abdominal support stockings may also dramatically reduce venous pooling.

In the less common hyperadrenergic form of POTS, patients may have orthostatic hypertension, tremulousness, cold, sweaty extremities, and anxiety due to an exaggerated response to beta‐adrenergic stimulation.7 The excessive sympathetic activity, which is poorly modulated by baroreflex activity, may be due to impaired mechanisms of norepinephrine reuptake by sympathetic ganglia.12 Consequently, serum norepinephrine levels are markedly elevated (>600 pg/mL).5

In adults, the presence of a POTS trigger is common and is usually an antecedent viral illness. Antibodies to the ganglionic acetylcholine receptor have been found in a subset of POTS patients,13 and this may suggest an idiopathic or postinflammatory autoimmune mechanism.14 This patient's presentation is unique because her symptoms developed after C5C6 spine surgery. The cervical spinal cord and sympathetic ganglia are dense with nerves involved in autonomic cardiovascular control, and damage to these fibers could explain the patient's physiology and symptoms. Among these, the descending vasomotor pathways traverse through the C5C8 area to innervate the splanchnic and leg venous circulation, receiving input from the heart along the way.15 The pattern of numbness and tingling fits the C5/C6 dermatomal distribution, as does the innervation of the radial artery. The frequent PVCs with a left bundle branch block pattern and inferior axis appear to arise from the right ventricular outflow tract and may be associated with regional sympathetic denervation, which has been described in idiopathic ventricular arrhythmias.16 POTS has been anecdotally reported after neck injury from motor vehicle accidents (whiplash), which is also thought to be related to cervical sympathetic nerve damage (B.P. Grubb, personal communication, 2005). Most cases of triggered POTS improve spontaneously after months to years, but this patient's prognosis remains uncertain because of the presumed mechanical disruption of the autonomic nerve fibers at the time of surgery.

This case demonstrates the complexities of arriving at a unifying diagnosis in the setting of a constellation of nonspecific symptoms and findings, some of which even suggest life‐threatening conditions. Because young women are primarily affected, symptoms of POTS can be mistakenly attributed to anxiety or other nonphysiological factors. A systematic approach excluded life‐threatening causes, including primary ventricular arrhythmias, coronary vasospasm, and coronary anomalies. The investigations narrowed the differential diagnosis, and the tilt‐table test confirmed POTS. Because the cardiac and circulatory dysautonomias encompass an array of distinct physiologic processes, understanding the patient's mechanism is critical to her management. The only effective therapies were those that counteracted venous pooling and improved venous return.

A30‐year‐old woman was referred for evaluation of chest pain, palpitations, and exercise intolerance. She had been previously healthy, active, and physically fit. Five months prior to our evaluation, she had an elective C5C6 cervical spine discectomy with interbody allograft fusion for a chronic neck injury that occurred 11 years ago during gymnastics. Two weeks after spine surgery, the patient developed numbness and tingling of her left thumb and palm that occurred with exertion or exposure to cold and subsided with rest. These episodes increased in frequency and intensity and after 1 week became associated with sharp, occasionally stabbing chest pain that radiated to the left arm. On one occasion, the patient had an episode of exertional chest pain with prolonged left arm cyanosis. Emergent left upper extremity angiography revealed normal great vessel anatomy with spasm of the radial artery and collateral ulnar flow. The patient was diagnosed with Raynaud's phenomenon and was started on nifedipine. A subsequent rheumatologic evaluation was unrevealing, and the patient was empirically switched to amlodipine with no improvement in symptoms.

This otherwise very healthy 30‐year‐old developed a multitude of symptoms. The patient's chest pain is atypical and in a young woman is unlikely to signify atherosclerotic coronary disease, but it should not be entirely disregarded. Vasospasm triggered by exposure to cold does raise suspicion for Raynaud's phenomenon, which is not uncommon in this demographic. However, this presentation is quite unusual because the vasospasm was limited to one vascular distribution of one extremity. Associated coronary vasospasm could explain the other symptoms, although coronary spasm is generally not associated with Raynaud's phenomenon. Vasculitis may also affect the pulmonary vasculature, leading to pulmonary hypertension and exercise intolerance. The temporal association with her spine surgery is intriguing but of unclear significance.

The patient continued to have frequent exertional episodes of sharp precordial chest pain radiating to her left arm that were accompanied by dyspnea and left upper extremity symptoms despite amlodipine therapy. These now occurred with limited activity when she walked 1 to 2 blocks uphill. Over the previous 2 months, she had also noticed palpitations occurring reliably with exercise that were relieved with 15 to 20 min of rest. With prolonged episodes, she reported dizziness, nausea, and blurry vision that improved with lying down. She twice had syncope with these symptoms. She noted lower extremity edema while taking calcium channel blockers, but this had resolved after discontinuation of the drugs.

The patient's past medical history included several high‐school orthopedic injuries. She had 2 kidney stones at ages 18 and 23 and had an appendectomy at age 28. Her only medication was an oral contraceptive, and she had discontinued the amlodipine. She denied the use of tobacco, alcohol, herbal medications, or illicit substances. There was no family history of sudden death or heart disease.

Palpitations in a 30‐year‐old woman may signify a cardiac arrhythmia. Paroxysmal supraventricular arrhythmias, such as atrioventricular nodal reentrant tachycardia, atrial tachycardia, and atrial fibrillation, are well described in the young. Ventricular tachycardia (VT) is another possible cause and could be idiopathic or related to occult structural heart disease. Young patients typically tolerate lone arrhythmias quite well, and her failure to do so raises suspicion for concomitant structural heart disease. Her palpitations may be from appropriate sinus tachycardia, which could be compensatory because of inadequate cardiac output reserve, which in turn could be caused by valvular disease, congenital heart disease, or ventricular dysfunction. The exertional chest pain is worrisome for ischemia. Pulmonary hypertension, severe ventricular hypertrophy, or congenital anomalies of the coronary circulation could lead to subendocardial myocardial ischemia with exertion, resulting in angina, dyspnea, and arrhythmias. However, the patient also experiences exertional palpitations without chest pain, which may signify an exertional tachyarrhythmia possibly mediated by catecholamines. Based solely on the history, the differential diagnosis remains broad.

On physical examination, the patient was a fit, thin, healthy woman. Her blood pressure was 120/70 mm Hg supine in both arms and 115/75 mm Hg standing; her pulse was 85 supine and 110 standing, Oxygen saturation was 100% on room air. A cardiac exam revealed a normal jugular venous pressure, normal point of maximal impulse, regular rhythm with occasional ectopy, normal S1, and physiologically split S2 without extra heart sounds or murmurs. The right ventricular impulse was faintly palpable at the left sternal border. Head, neck, chest, abdominal, musculoskeletal, neurologic, extremity, and peripheral pulse examinations were normal.

Laboratory data showed a normal complete blood count and normal chemistries. Serum tests for hepatitis C antibody, cardiolipin antibody, rheumatoid factor, cryoglobulins, and anti‐nuclear antibody were negative. The erythrocyte sedimentation rate and thyroid stimulating hormone levels were within normal limits. An electrocardiogram (ECG) demonstrated a normal sinus rhythm with frequent premature ventricular complexes (PVCs) and normal axis and intervals. (Figure 1). The PR segment was normal and without preexcitation. A prior ECG from 3 months ago was similar with ventricular trigeminy.

Figure 1

Her unremarkable cardiac examination does not favor structural or valvular heart disease, and there are no obvious stigmata of vasculitis. She did become mildly tachycardic upon standing, and this raises the possibility of orthostatic tachycardia. A comprehensive rheumatologic panel revealed no evidence of autoimmune disease or vasculitis, and the clinical constellation is not consistent with primary or secondary Raynaud's disease. The ECG demonstrates frequent monomorphic PVCs complexes with a left bundle branch block pattern and an inferior axis. This pattern suggests that the PVCs arise from the right ventricular outflow tract. Idiopathic right ventricular outflow tract VT and arrhythmogenic right ventricular dysplasia must be considered as a cause of exertional or catecholamine‐mediated tachycardia. The normal ECG argues against arrhythmogenic right ventricular dysplasia, in which patients typically have incomplete or complete right bundle branch block, right precordial T wave abnormalities, and occasionally epsilon waves. Her QT interval is normal, but excluding long‐QT syndrome with a single ECG has poor sensitivity. The next critical step is to document her cardiac rhythm during symptoms and to exclude malignant arrhythmias.

An event recorder and exercise echocardiogram were ordered. While the patient was wearing her event recorder, she had 4 episodes of exertional syncope while hiking and successfully triggered event recording before losing consciousness. She had chest pain and left arm pain after regaining consciousness. The patient came to the emergency room for evaluation. Her blood pressure was 116/80 mm Hg supine and 112/70 mm Hg seated. Her heart rate increased from 82 supine to 132 seated. The physical examination was unremarkable. ECG showed sinus rhythm with frequent PVCs. Troponin‐I measurements 10 hours apart were 0.7 and 0.3 g/L (normal < 1.1), with normal creatinine kinase and creatinine kinase MB fractions. Interrogation of the event recorder revealed multiple episodes of a narrow complex tachycardia with rates up to 180 bpm that correlated with symptoms (Figure 2). There were no episodes of wide complex tachycardia.

Figure 2

The patient was not hypotensive in the emergency room, but she had evidence of a marked orthostatic tachycardia. The minimal but significant troponin elevations are also troubling. Although her clinical picture is not consistent with an acute coronary syndrome, I am concerned about other mechanisms of myocardial ischemia or injury, such as a coronary anomaly or subendocardial ischemia from globally reduced myocardial perfusion. The presence of event recorder data from her syncopal events was fortuitous and revealed a supraventricular tachycardia. The arrhythmia was gradual in onset and resolution and had no triggers, such as premature atrial or ventricular complexes, which could suggest reentrant arrhythmias. The P wave morphology was also unchanged, and this argues against an atrial tachycardia. These findings are consistent with sinus tachycardia, which was notably out of proportion to her workload. This arrhythmia may be the primary cause of syncope, such as in inappropriate sinus tachycardia, or it may be a compensatory mechanism. Tachycardia from coronary vasospasm is often preceded by ST segment changes, which are not seen here. Although the event recorder had no episodes of VT, the patient's persistent frequent PVCs are still of concern. I would obtain an echocardiogram to exclude structural heart disease and an exercise test to exclude exertional VT. Finally, coronary angiography may be helpful in excluding congenital anomalies.

The patient was admitted for evaluation. An exercise treadmill test was performed, and the patient exercised 20 min on the standard Bruce protocol with a peak heart rate of 180 bpm. The test was notable for a premature rise in heart rate (in stage 1) without a rise in blood pressure. There were no symptoms or ST/T wave changes. Transthoracic echocardiogram showed normal left ventricular size and function with normal anatomy, valves, and hemodynamics. Coronary angiography showed a right dominant system with normal anatomy and no atherosclerotic disease.

Ventricular arrhythmias could not be elicited with exercise. Her high exercise tolerance virtually excluded hemodynamically significant structural or valvular disease, and this was confirmed by the echocardiogram. Coronary angiography excluded coronary anomalies and myocardial bridging. The most intriguing finding is the rise in the patient's heart rate out of proportion to the workload. This, along with her orthostatic tachycardia, raises the issue of inappropriate sinus tachycardia or postural orthostatic tachycardia syndrome (POTS). Carotid hypersensitivity is also a possibility. The patient was hiking when she fainted, and even light pressure on the patient's neck with head turning or from a camera strap, for example, could produce syncope. Although carotid hypersensitivity usually results in sinus bradycardia and AV block, it may be followed by reflex tachycardia, which was seen in this patient's event recordings. I would perform a tilt‐table test with carotid massage to make the diagnosis.

Tilt‐table testing was performed (Figure 3). Her supine blood pressure was 128/68 mm Hg, and her heart rate was 72 bpm with no change during the 10‐min supine period. Upon elevation to a 70‐degree tilt, the patient had an immediate increase in her heart rate to 160 bpm with a blood pressure nadir of 109/58 mm Hg and symptoms of palpitations, dizziness, dyspnea, chest pain, blurry vision, and nausea. Her peak heart rate was 172 bpm, and her peak blood pressure was 122/72 mm Hg. Vital signs did not change in response to carotid sinus massage in the supine or upright positions.

Figure 3

The tilt‐table test has 3 notable findings. First, her heart rate increased rapidly with tilt and decreased rapidly in supine recovery. Second, her usual symptoms started immediately after tilt and quickly resolved in recovery when vital signs returned to baseline. Finally, there was only a modest drop in blood pressure. These findings are classic for POTS. POTS is defined as symptomatic orthostasis with a heart rate increase of 30 bpm or a heart rate of 120 bpm. The physiologic lesions found in the syndrome are heterogeneous, but they all lead to a failure of orthostatic compensation. In POTS, the tachycardia is a reflex secondary to hypotension (baroreceptor reflex) or reduced preload (cardiac mechanoreceptors), in contrast to inappropriate sinus tachycardia. Interestingly, blood pressure is usually preserved until the final moments preceding syncope, when venous return further declines, tachycardia decreases the diastolic filling time and stroke volume, and mean arterial pressure sharply falls.

The patient was started on labetalol (200 mg 3 times daily), and her symptoms worsened. She also developed nausea and constipation. Midodrine and pindolol were also tried without success. She was then switched to fludrocortisone, salt supplementation, and leg support stockings with dramatic improvement.

COMMENTARY

In 1871, DeCosta1 published a report on the irritable heart, noting an affliction of extreme fatigue and exercise intolerance that occurred suddenly and without obvious cause. Subsequently, the terms vasoregulatory asthenia and neurocirculatory asthenia were used to link cardiovascular symptoms to impaired regulation of peripheral blood flow.2, 3 The term POTS was first used in 1982 to describe a single patient with postural tachycardia without hypotension and palpitations, weakness, abdominal pain, and presyncope.4

POTS is one of several disorders of autonomic control associated with orthostatic intolerance. The criteria for diagnosis are listed in Table 1. POTS typically occurs in women between the ages of 15 and 50 but tends to present during adolescence or young adulthood. The physiology has only recently been elucidated. When a person stands, 500 cc of the total blood volume is displaced to the dependent extremities and inferior mesenteric vessels.5 Normally, orthostatic stabilization occurs in less than 1 minute via 3 mechanisms: baroreceptor input, sympathetic reflex tachycardia and vasoconstriction, and enhanced venous return via the pumping action of skeletal muscles and venoconstriction. In POTS, there is a failure of at least one of these mechanisms, leading to decreased venous return, a 40% reduction in stroke volume, and cerebral hypoperfusion.6

POTS is divided into 2 major subtypes on the basis of pathophysiology.5, 7 The partial dysautonomic form is the most common and the type that this patient most likely had. In this form, the development of an acquired peripheral autonomic neuropathy results in a failure of sympathetic venoconstriction, which leads to excessive venous pooling in the lower extremities and splanchnic circulation.8, 9 Failure to mobilize this venous reservoir upon standing leads to excessive orthostatic tachycardia secondary to a marked reduction in stroke volume. Peripheral arterial vasoconstriction is generally preserved, which is why midodrine, an arterial vasoconstrictor, did not improve symptoms. The labetalol may have further exacerbated peripheral pooling because of its alpha‐adrenergic blocking properties. Because total plasma volume is decreased and plasma renin activity is inappropriately low,10 volume expanders, including salt, low‐dose steroids, and fluids, can attenuate symptoms.11 The extrinsic venous compression from leg and abdominal support stockings may also dramatically reduce venous pooling.

In the less common hyperadrenergic form of POTS, patients may have orthostatic hypertension, tremulousness, cold, sweaty extremities, and anxiety due to an exaggerated response to beta‐adrenergic stimulation.7 The excessive sympathetic activity, which is poorly modulated by baroreflex activity, may be due to impaired mechanisms of norepinephrine reuptake by sympathetic ganglia.12 Consequently, serum norepinephrine levels are markedly elevated (>600 pg/mL).5

In adults, the presence of a POTS trigger is common and is usually an antecedent viral illness. Antibodies to the ganglionic acetylcholine receptor have been found in a subset of POTS patients,13 and this may suggest an idiopathic or postinflammatory autoimmune mechanism.14 This patient's presentation is unique because her symptoms developed after C5C6 spine surgery. The cervical spinal cord and sympathetic ganglia are dense with nerves involved in autonomic cardiovascular control, and damage to these fibers could explain the patient's physiology and symptoms. Among these, the descending vasomotor pathways traverse through the C5C8 area to innervate the splanchnic and leg venous circulation, receiving input from the heart along the way.15 The pattern of numbness and tingling fits the C5/C6 dermatomal distribution, as does the innervation of the radial artery. The frequent PVCs with a left bundle branch block pattern and inferior axis appear to arise from the right ventricular outflow tract and may be associated with regional sympathetic denervation, which has been described in idiopathic ventricular arrhythmias.16 POTS has been anecdotally reported after neck injury from motor vehicle accidents (whiplash), which is also thought to be related to cervical sympathetic nerve damage (B.P. Grubb, personal communication, 2005). Most cases of triggered POTS improve spontaneously after months to years, but this patient's prognosis remains uncertain because of the presumed mechanical disruption of the autonomic nerve fibers at the time of surgery.

This case demonstrates the complexities of arriving at a unifying diagnosis in the setting of a constellation of nonspecific symptoms and findings, some of which even suggest life‐threatening conditions. Because young women are primarily affected, symptoms of POTS can be mistakenly attributed to anxiety or other nonphysiological factors. A systematic approach excluded life‐threatening causes, including primary ventricular arrhythmias, coronary vasospasm, and coronary anomalies. The investigations narrowed the differential diagnosis, and the tilt‐table test confirmed POTS. Because the cardiac and circulatory dysautonomias encompass an array of distinct physiologic processes, understanding the patient's mechanism is critical to her management. The only effective therapies were those that counteracted venous pooling and improved venous return.

A30‐year‐old woman was referred for evaluation of chest pain, palpitations, and exercise intolerance. She had been previously healthy, active, and physically fit. Five months prior to our evaluation, she had an elective C5C6 cervical spine discectomy with interbody allograft fusion for a chronic neck injury that occurred 11 years ago during gymnastics. Two weeks after spine surgery, the patient developed numbness and tingling of her left thumb and palm that occurred with exertion or exposure to cold and subsided with rest. These episodes increased in frequency and intensity and after 1 week became associated with sharp, occasionally stabbing chest pain that radiated to the left arm. On one occasion, the patient had an episode of exertional chest pain with prolonged left arm cyanosis. Emergent left upper extremity angiography revealed normal great vessel anatomy with spasm of the radial artery and collateral ulnar flow. The patient was diagnosed with Raynaud's phenomenon and was started on nifedipine. A subsequent rheumatologic evaluation was unrevealing, and the patient was empirically switched to amlodipine with no improvement in symptoms.

This otherwise very healthy 30‐year‐old developed a multitude of symptoms. The patient's chest pain is atypical and in a young woman is unlikely to signify atherosclerotic coronary disease, but it should not be entirely disregarded. Vasospasm triggered by exposure to cold does raise suspicion for Raynaud's phenomenon, which is not uncommon in this demographic. However, this presentation is quite unusual because the vasospasm was limited to one vascular distribution of one extremity. Associated coronary vasospasm could explain the other symptoms, although coronary spasm is generally not associated with Raynaud's phenomenon. Vasculitis may also affect the pulmonary vasculature, leading to pulmonary hypertension and exercise intolerance. The temporal association with her spine surgery is intriguing but of unclear significance.

The patient continued to have frequent exertional episodes of sharp precordial chest pain radiating to her left arm that were accompanied by dyspnea and left upper extremity symptoms despite amlodipine therapy. These now occurred with limited activity when she walked 1 to 2 blocks uphill. Over the previous 2 months, she had also noticed palpitations occurring reliably with exercise that were relieved with 15 to 20 min of rest. With prolonged episodes, she reported dizziness, nausea, and blurry vision that improved with lying down. She twice had syncope with these symptoms. She noted lower extremity edema while taking calcium channel blockers, but this had resolved after discontinuation of the drugs.

The patient's past medical history included several high‐school orthopedic injuries. She had 2 kidney stones at ages 18 and 23 and had an appendectomy at age 28. Her only medication was an oral contraceptive, and she had discontinued the amlodipine. She denied the use of tobacco, alcohol, herbal medications, or illicit substances. There was no family history of sudden death or heart disease.

Palpitations in a 30‐year‐old woman may signify a cardiac arrhythmia. Paroxysmal supraventricular arrhythmias, such as atrioventricular nodal reentrant tachycardia, atrial tachycardia, and atrial fibrillation, are well described in the young. Ventricular tachycardia (VT) is another possible cause and could be idiopathic or related to occult structural heart disease. Young patients typically tolerate lone arrhythmias quite well, and her failure to do so raises suspicion for concomitant structural heart disease. Her palpitations may be from appropriate sinus tachycardia, which could be compensatory because of inadequate cardiac output reserve, which in turn could be caused by valvular disease, congenital heart disease, or ventricular dysfunction. The exertional chest pain is worrisome for ischemia. Pulmonary hypertension, severe ventricular hypertrophy, or congenital anomalies of the coronary circulation could lead to subendocardial myocardial ischemia with exertion, resulting in angina, dyspnea, and arrhythmias. However, the patient also experiences exertional palpitations without chest pain, which may signify an exertional tachyarrhythmia possibly mediated by catecholamines. Based solely on the history, the differential diagnosis remains broad.

On physical examination, the patient was a fit, thin, healthy woman. Her blood pressure was 120/70 mm Hg supine in both arms and 115/75 mm Hg standing; her pulse was 85 supine and 110 standing, Oxygen saturation was 100% on room air. A cardiac exam revealed a normal jugular venous pressure, normal point of maximal impulse, regular rhythm with occasional ectopy, normal S1, and physiologically split S2 without extra heart sounds or murmurs. The right ventricular impulse was faintly palpable at the left sternal border. Head, neck, chest, abdominal, musculoskeletal, neurologic, extremity, and peripheral pulse examinations were normal.

Laboratory data showed a normal complete blood count and normal chemistries. Serum tests for hepatitis C antibody, cardiolipin antibody, rheumatoid factor, cryoglobulins, and anti‐nuclear antibody were negative. The erythrocyte sedimentation rate and thyroid stimulating hormone levels were within normal limits. An electrocardiogram (ECG) demonstrated a normal sinus rhythm with frequent premature ventricular complexes (PVCs) and normal axis and intervals. (Figure 1). The PR segment was normal and without preexcitation. A prior ECG from 3 months ago was similar with ventricular trigeminy.

Figure 1

Her unremarkable cardiac examination does not favor structural or valvular heart disease, and there are no obvious stigmata of vasculitis. She did become mildly tachycardic upon standing, and this raises the possibility of orthostatic tachycardia. A comprehensive rheumatologic panel revealed no evidence of autoimmune disease or vasculitis, and the clinical constellation is not consistent with primary or secondary Raynaud's disease. The ECG demonstrates frequent monomorphic PVCs complexes with a left bundle branch block pattern and an inferior axis. This pattern suggests that the PVCs arise from the right ventricular outflow tract. Idiopathic right ventricular outflow tract VT and arrhythmogenic right ventricular dysplasia must be considered as a cause of exertional or catecholamine‐mediated tachycardia. The normal ECG argues against arrhythmogenic right ventricular dysplasia, in which patients typically have incomplete or complete right bundle branch block, right precordial T wave abnormalities, and occasionally epsilon waves. Her QT interval is normal, but excluding long‐QT syndrome with a single ECG has poor sensitivity. The next critical step is to document her cardiac rhythm during symptoms and to exclude malignant arrhythmias.

An event recorder and exercise echocardiogram were ordered. While the patient was wearing her event recorder, she had 4 episodes of exertional syncope while hiking and successfully triggered event recording before losing consciousness. She had chest pain and left arm pain after regaining consciousness. The patient came to the emergency room for evaluation. Her blood pressure was 116/80 mm Hg supine and 112/70 mm Hg seated. Her heart rate increased from 82 supine to 132 seated. The physical examination was unremarkable. ECG showed sinus rhythm with frequent PVCs. Troponin‐I measurements 10 hours apart were 0.7 and 0.3 g/L (normal < 1.1), with normal creatinine kinase and creatinine kinase MB fractions. Interrogation of the event recorder revealed multiple episodes of a narrow complex tachycardia with rates up to 180 bpm that correlated with symptoms (Figure 2). There were no episodes of wide complex tachycardia.

Figure 2

The patient was not hypotensive in the emergency room, but she had evidence of a marked orthostatic tachycardia. The minimal but significant troponin elevations are also troubling. Although her clinical picture is not consistent with an acute coronary syndrome, I am concerned about other mechanisms of myocardial ischemia or injury, such as a coronary anomaly or subendocardial ischemia from globally reduced myocardial perfusion. The presence of event recorder data from her syncopal events was fortuitous and revealed a supraventricular tachycardia. The arrhythmia was gradual in onset and resolution and had no triggers, such as premature atrial or ventricular complexes, which could suggest reentrant arrhythmias. The P wave morphology was also unchanged, and this argues against an atrial tachycardia. These findings are consistent with sinus tachycardia, which was notably out of proportion to her workload. This arrhythmia may be the primary cause of syncope, such as in inappropriate sinus tachycardia, or it may be a compensatory mechanism. Tachycardia from coronary vasospasm is often preceded by ST segment changes, which are not seen here. Although the event recorder had no episodes of VT, the patient's persistent frequent PVCs are still of concern. I would obtain an echocardiogram to exclude structural heart disease and an exercise test to exclude exertional VT. Finally, coronary angiography may be helpful in excluding congenital anomalies.

The patient was admitted for evaluation. An exercise treadmill test was performed, and the patient exercised 20 min on the standard Bruce protocol with a peak heart rate of 180 bpm. The test was notable for a premature rise in heart rate (in stage 1) without a rise in blood pressure. There were no symptoms or ST/T wave changes. Transthoracic echocardiogram showed normal left ventricular size and function with normal anatomy, valves, and hemodynamics. Coronary angiography showed a right dominant system with normal anatomy and no atherosclerotic disease.

Ventricular arrhythmias could not be elicited with exercise. Her high exercise tolerance virtually excluded hemodynamically significant structural or valvular disease, and this was confirmed by the echocardiogram. Coronary angiography excluded coronary anomalies and myocardial bridging. The most intriguing finding is the rise in the patient's heart rate out of proportion to the workload. This, along with her orthostatic tachycardia, raises the issue of inappropriate sinus tachycardia or postural orthostatic tachycardia syndrome (POTS). Carotid hypersensitivity is also a possibility. The patient was hiking when she fainted, and even light pressure on the patient's neck with head turning or from a camera strap, for example, could produce syncope. Although carotid hypersensitivity usually results in sinus bradycardia and AV block, it may be followed by reflex tachycardia, which was seen in this patient's event recordings. I would perform a tilt‐table test with carotid massage to make the diagnosis.

Tilt‐table testing was performed (Figure 3). Her supine blood pressure was 128/68 mm Hg, and her heart rate was 72 bpm with no change during the 10‐min supine period. Upon elevation to a 70‐degree tilt, the patient had an immediate increase in her heart rate to 160 bpm with a blood pressure nadir of 109/58 mm Hg and symptoms of palpitations, dizziness, dyspnea, chest pain, blurry vision, and nausea. Her peak heart rate was 172 bpm, and her peak blood pressure was 122/72 mm Hg. Vital signs did not change in response to carotid sinus massage in the supine or upright positions.

Figure 3

The tilt‐table test has 3 notable findings. First, her heart rate increased rapidly with tilt and decreased rapidly in supine recovery. Second, her usual symptoms started immediately after tilt and quickly resolved in recovery when vital signs returned to baseline. Finally, there was only a modest drop in blood pressure. These findings are classic for POTS. POTS is defined as symptomatic orthostasis with a heart rate increase of 30 bpm or a heart rate of 120 bpm. The physiologic lesions found in the syndrome are heterogeneous, but they all lead to a failure of orthostatic compensation. In POTS, the tachycardia is a reflex secondary to hypotension (baroreceptor reflex) or reduced preload (cardiac mechanoreceptors), in contrast to inappropriate sinus tachycardia. Interestingly, blood pressure is usually preserved until the final moments preceding syncope, when venous return further declines, tachycardia decreases the diastolic filling time and stroke volume, and mean arterial pressure sharply falls.

The patient was started on labetalol (200 mg 3 times daily), and her symptoms worsened. She also developed nausea and constipation. Midodrine and pindolol were also tried without success. She was then switched to fludrocortisone, salt supplementation, and leg support stockings with dramatic improvement.

COMMENTARY

In 1871, DeCosta1 published a report on the irritable heart, noting an affliction of extreme fatigue and exercise intolerance that occurred suddenly and without obvious cause. Subsequently, the terms vasoregulatory asthenia and neurocirculatory asthenia were used to link cardiovascular symptoms to impaired regulation of peripheral blood flow.2, 3 The term POTS was first used in 1982 to describe a single patient with postural tachycardia without hypotension and palpitations, weakness, abdominal pain, and presyncope.4

POTS is one of several disorders of autonomic control associated with orthostatic intolerance. The criteria for diagnosis are listed in Table 1. POTS typically occurs in women between the ages of 15 and 50 but tends to present during adolescence or young adulthood. The physiology has only recently been elucidated. When a person stands, 500 cc of the total blood volume is displaced to the dependent extremities and inferior mesenteric vessels.5 Normally, orthostatic stabilization occurs in less than 1 minute via 3 mechanisms: baroreceptor input, sympathetic reflex tachycardia and vasoconstriction, and enhanced venous return via the pumping action of skeletal muscles and venoconstriction. In POTS, there is a failure of at least one of these mechanisms, leading to decreased venous return, a 40% reduction in stroke volume, and cerebral hypoperfusion.6

POTS is divided into 2 major subtypes on the basis of pathophysiology.5, 7 The partial dysautonomic form is the most common and the type that this patient most likely had. In this form, the development of an acquired peripheral autonomic neuropathy results in a failure of sympathetic venoconstriction, which leads to excessive venous pooling in the lower extremities and splanchnic circulation.8, 9 Failure to mobilize this venous reservoir upon standing leads to excessive orthostatic tachycardia secondary to a marked reduction in stroke volume. Peripheral arterial vasoconstriction is generally preserved, which is why midodrine, an arterial vasoconstrictor, did not improve symptoms. The labetalol may have further exacerbated peripheral pooling because of its alpha‐adrenergic blocking properties. Because total plasma volume is decreased and plasma renin activity is inappropriately low,10 volume expanders, including salt, low‐dose steroids, and fluids, can attenuate symptoms.11 The extrinsic venous compression from leg and abdominal support stockings may also dramatically reduce venous pooling.

In the less common hyperadrenergic form of POTS, patients may have orthostatic hypertension, tremulousness, cold, sweaty extremities, and anxiety due to an exaggerated response to beta‐adrenergic stimulation.7 The excessive sympathetic activity, which is poorly modulated by baroreflex activity, may be due to impaired mechanisms of norepinephrine reuptake by sympathetic ganglia.12 Consequently, serum norepinephrine levels are markedly elevated (>600 pg/mL).5

In adults, the presence of a POTS trigger is common and is usually an antecedent viral illness. Antibodies to the ganglionic acetylcholine receptor have been found in a subset of POTS patients,13 and this may suggest an idiopathic or postinflammatory autoimmune mechanism.14 This patient's presentation is unique because her symptoms developed after C5C6 spine surgery. The cervical spinal cord and sympathetic ganglia are dense with nerves involved in autonomic cardiovascular control, and damage to these fibers could explain the patient's physiology and symptoms. Among these, the descending vasomotor pathways traverse through the C5C8 area to innervate the splanchnic and leg venous circulation, receiving input from the heart along the way.15 The pattern of numbness and tingling fits the C5/C6 dermatomal distribution, as does the innervation of the radial artery. The frequent PVCs with a left bundle branch block pattern and inferior axis appear to arise from the right ventricular outflow tract and may be associated with regional sympathetic denervation, which has been described in idiopathic ventricular arrhythmias.16 POTS has been anecdotally reported after neck injury from motor vehicle accidents (whiplash), which is also thought to be related to cervical sympathetic nerve damage (B.P. Grubb, personal communication, 2005). Most cases of triggered POTS improve spontaneously after months to years, but this patient's prognosis remains uncertain because of the presumed mechanical disruption of the autonomic nerve fibers at the time of surgery.

This case demonstrates the complexities of arriving at a unifying diagnosis in the setting of a constellation of nonspecific symptoms and findings, some of which even suggest life‐threatening conditions. Because young women are primarily affected, symptoms of POTS can be mistakenly attributed to anxiety or other nonphysiological factors. A systematic approach excluded life‐threatening causes, including primary ventricular arrhythmias, coronary vasospasm, and coronary anomalies. The investigations narrowed the differential diagnosis, and the tilt‐table test confirmed POTS. Because the cardiac and circulatory dysautonomias encompass an array of distinct physiologic processes, understanding the patient's mechanism is critical to her management. The only effective therapies were those that counteracted venous pooling and improved venous return.

A 60 year‐old woman with advanced kidney disease presented with one month of progressively worsening, sharp burning pain and decreased sensation in her left hand. Cold air exacerbated the pain. She noted decreasing ability to utilize her left fingers, a weakened grip and that the muscles in her hand looked smaller.

Localized sensory and motor symptoms in a discrete region of a single limb suggest neuropathy. The lack of symptoms in the face or ipsilateral lower extremity would dissuade a clinician from considering central etiologies; the presence of neuropathic pain is uncommon for cortical lesions. The involvement of motor and sensory nerves indicates peripheral nerve involvement.

The general approach to patients with peripheral neuropathy begins with identifying the neuropathy as a mononeuropathy (involving a single nerve), a polyneuropathy (symmetric involvement of multiple nerves) or a mononeuropathy multiplex (asymmetric involvement of multiple nerves). The patient, in this case, described subacute neuropathic pain, sensory loss, and weakness in her left hand in a distribution consistent with mononeuropathy or mononeuropathy multiplex.

This patient could have carpal tunnel syndrome given its prevalence in patients with advanced renal disease. The differential diagnosis is broad, however, and includes ulnar mononeuropathy, nerve ischemia due to vasculitis or vasculopathy, lower cervical radiculopathy (though the patient does not describe neck or radicular pain), lower brachial plexopathy, and complex regional pain syndrome.

The patient was diagnosed with advanced kidney disease one year ago when biopsy revealed focal segmental glomerulosclerosis secondary to lithium. Since her diagnosis, two grafts were placed in the left upper arm in anticipation of dialysis: the first, placed seven months prior to this admission, failed to mature; the second, placed one month prior to this admission, was complicated by bleeding at the fistula site and was not yet mature. Prior to this admission she had not required hemodialysis. Her past history included hypertension, dyslipidemia, hypothyroidism, secondary hyperparathyroidism, a remote history of cervical cancer (stage unknown, recent PAP smear negative), microcytosis and schizoaffective disorder. Her medications were furosemide, amlodipine, lisinopril, atenolol, atorvastatin, pantoprazole, olanzapine, levothyroxine, iron, darbepoetin, sevelamer, multivitamin and docusate.

Given the history of procedures in the left arm one should consider ischemic injury to the left median nerve. Other local complications could include compressive lesions such as an abscess or hematoma or direct nerve injury from the procedure. Carpal tunnel syndrome remains high on the differential due to its prevalence and because renal failure and hypothyroidism increase the risk of carpal tunnel syndrome.

A careful physical examination would localize the nerve or nerves involved. Examination findings that would be consistent with carpal tunnel syndrome include sensory loss in the distribution of the left median nerve, weakness of muscles innervated by the median nerve, including the abductor pollicus brevis and opponens muscles, and a Tinels and Phalens sign of the left wrist. A proximal median neuropathy resulting from ischemia or compression might also involve median‐innervated forearm muscle such as the pronator teres (forearm pronation) and flexor carpi radialis (hand flexion and abduction) muscles. Complex regional pain syndrome can be seen after a traumatic injury or surgery and is typified by severe neuropathic pain in a limb, often in combination with trophic changes in the affected extremity. A cervical radiculopathy would affect muscles supplied by the injured nerve root. For example, a C8 radiculopathy would affect all of the intrinsic hand muscles, the wrist and finger extensors, and the triceps brachii. A lower brachial plexopathy would present similarly to a lower cervical radiculopathy on clinical examination; electrodiagnostic evaluation would be necessary to distinguish these two disorders.

The patient appeared fatigued and her left hand was wrapped in blankets. Her vital signs were stable. There was no thyroid enlargement or lymphadenopathy. There was marked thenar, hypothenar and forearm atrophy on the left. Strength testing of her left hand demonstrated a grip strength of 2/5, finger extension and interosseous strength of 1/5, left wrist flexion and extension of 3/5; left biceps and triceps were 5/5. Sensation was mildly decreased to light touch, temperature, pain and proprioception throughout the left hand. Strength and sensation were intact in the right upper and bilateral lower extremities. Reflexes were 2+ throughout. The left radial pulse was diminished compared to the left ulnar that was 1+. The left hand was dry and cool. Laboratory evaluation revealed an elevated white blood cell count of 15,300/mm³, a hematocrit of 33 percent, mean corpuscular volume of 73 fL, and a normal platelet count. Electrolytes were consistent with advanced renal disease. The thyroid stimulating hormone level was normal.

The patient's examination reveals an injury to the sensory and motor components of the left ulnar, median, and distal radial nerves. The volar forearm wasting suggests proximal median motor nerve injury in the forearm. Because the triceps is spared, the weakness of finger and wrist extension implies distal radial motor nerve injury. The interosseous weakness is consistent with injury to the ulnar motor nerve. Weakness of grip and wrist flexion is less specific and it may be explained by injury to either the median or ulnar motor nerves. The diffuse sensory loss over the palmar and dorsal aspect of the left hand is consistent with neuropathic injury to the left median, ulnar, and radial sensory nerves. The preserved deep tendon reflexes are controlled by the musculocutaneous nerve (the biceps reflex) and branches arising from the proximal radial nerve (the triceps and brachioradialis reflexes), both of which are proximal to the apparent level of neuropathic insult.

Carpal tunnel syndrome is excluded since abnormalities extend beyond the median nerve distribution. The presentation is consistent with a mononeuropathy multiplex. Axonal etiologies of mononeuropathy multiplexincluding vasculitis, ischemia, neoplastic infiltration, and infectious etiologies such as Lyme diseaseare more common than demyelinating causes. Vasculitic neuropathy commonly involves the lower extremities and may have systemic symptoms, not present in this case. Neoplasm or other compressive lesions such as hematoma could explain these findings. Abscess must be considered given the leukocytosis. A lower brachial plexopathy, technically a mononeuropathy multiplex involving the proximal arm at the level of the brachial plexus, is also in the differential diagnosis. Another axonal disorder to consider would be neuralgic amyotrophy, an idiopathic form of acute brachial plexopathy associated with pain that is a complication of surgery that typically presents within a few hours to weeks of the procedure.

Demyelinating causes of mononeuropathy multiplex are less likely and include a variant of chronic inflammatory demyelinating polyneuropathy (Lewis‐Sumner syndrome) and hereditary neuropathy with liability to pressure palsies. Both processes are typically indolent and usually not painful, though the latter may present with fulminant numbness and weakness.

Nerve conduction and needle electromyography of the arm and cervical paraspinal muscles would differentiate axonal degeneration from demyelination. It would identify the affected nerves and any nerve root involvement. Given the concern for abscess or hematoma, MR neurography focused on the surgical site would also be important.

Electromyography and nerve conduction velocities demonstrated severe axonal loss of the left median, ulnar and distal radial sensory nerves consistent with acute denervation. A magnetic resonance neurogram following the course of these nerves revealed enlarged ulnar and median nerves with abnormal signal, but no compressive lesion (Fig. 1).

Figure 1

The electrodiagnostic testing is consistent with severe acute axonal injury to the left ulnar, median and radial nerves. This supports a diagnosis of mononeuropathy multiplex with axonal injury. Demyelinating causes are excluded at this point.

The MR neurogram demonstrates nonspecific nerve enlargement, which may be seen in ischemia, neoplastic processes (primary or metastatic), demyelinating disease, or, rarely, amyloidosis. Neoplastic involvement is unlikely in this case given the absence of a compressive mass lesion and the long segmental involvement of both the median and ulnar nerves. Compression from an abscess or hematoma is excluded. Neuralgic amyotrophy does not typically cause nerve enlargement.

Ischemia is the most likely diagnosis. Laboratory evaluation for vasculitis would be reasonable. Vasculitides that could present in this fashion include: polyarteritis nodosa, mixed connective tissue disease, Wegner's granulomatosis, Churg‐Strauss angiitis, Sjogren's, hepatitis C with serum cryoglobulinemia and possibly rheumatoid arthritis. Given the history of fistula placement in the affected limb, vascular sufficiency must be assessed.

Anti‐nuclear antibodies and anti‐neutrophilic cytoplasmic antibodies were negative, and a C‐ reactive protein was 5.9 mg/L (normal range, 0 to 10 mg/L). The erythrocyte sedimentation rate was 32mm/hr (normal range, 0 to 20) and serologies for hepatitis B and C were negative. There was no evidence of serum cryoglobulins.

A modestly elevated sedimentation rate and normal C‐reactive protein argue against a diagnosis of vasculitis. The negative ANA, ANCA, hepatitis serologies and cryoglobulin tests render unlikely the diagnoses of polyarteritis nodosa, Wegner's granulomatosis, Churg‐Strauss angiitis, or hepatitis related cryoglobulinemia. Eosinophilia (present in Churg‐Strauss), ENA (positive in mixed connective tissue disease), anti‐SSA and SSB (positive in Sjogren's) and a rheumatoid factor would round out this evaluation for vasculitis. A left radial sensory nerve biopsy could also be of value in diagnosing vasculitic neuropathy in this patient.

Given the evidence against vasculitis, the possibility of ischemia due to vascular insufficiency is concerning. Two ischemic complications of hemodialysis are known to cause distal multiple mononeuropathies. The first, ischemic monomelic neuropathy syndrome is seen almost exclusively in diabetics. It is characterized by the development of acute pain, weakness of the forearm and hand muscles, and sensory loss within minutes or hours of AV graft placement. Transient occlusion of the blood supply to the nerves of the forearm and hand induces nerve ischemia, but does not cause necrosis of other tissues. The nerve conduction findings in this patient are consistent with ischemic monomelic neuropathy syndrome. The delayed onset of her symptoms, however, makes this diagnosis unlikely.

The second ischemic complication of hemodialysis, and the likelier diagnosis, is vascular steal syndrome. This has a similar clinical and electrodiagnostic presentation to ischemic monomelic neuropathy syndrome, but has a latency period after surgery of days to months. Vascular steal occurs when a reversal of blood flow into the fistula steals flow from the palmar arch arteries and induces ischemia of the vasa nervorum. Vascular studies should be obtained urgently when this diagnosis is considered.

Evaluation of the arteriovenous graft and vascular surgery consultation were sought. Digital photoplethysmography revealed diminished waveforms in all fingers of the left hand. Arterial Doppler evaluation of the left upper extremity confirmed low‐velocity flow in the radial and ulnar arteries and failed to confirm flow in the brachial artery distal to the arteriovenous fistula. The patient underwent an angiogram of the left axillary and brachial arteries. There was normal flow until the level of the arteriovenous fistula but minimal flow distal to the fistula (Fig. 2).

Figure 2

The diminished waveforms on digital photoplethysmography are consistent with poor perfusion distally. The angiogram suggests that the multiple mononeuropathies are a consequence of ischemia from impaired blood flow.

Consulting the vascular surgeons in this setting is essential because restoring adequate blood flow to the affected nerves can prevent further loss of function. Prognosis is dependent on many factors, including the severity of the functional loss and the duration of the symptoms prior to the restoration of blood flow. The patient's severe weakness and substantial muscle atrophy, manifestations of axonal degeneration, imply a poorer prognosis for recovery of function.

Embolization of the arteriovenous fistula was performed by interventional radiology. Post embolization angiograms demonstrated improved peripheral arterial flow (Fig. 3). One day later, the patient's finger flexion and extension improved. She reported mildly decreased dysesthesias and on examination her fingers were warmer to the touch. One month after discharge, her strength continued to be impaired, though improved and she still experienced pain.

Figure 3

COMMENTARY

Hospitalists must be equipped to recognize urgent and potentially reversible causes of neuropathy. The hospitalist should maintain a high index of suspicion for ischemia (either due to vasculitis or vascular compromise), traumatic nerve injury, nerve compression or entrapment, lymphoma or metastatic infiltration, hepatitis C with cryoglobulinemia, Guillain‐Barre syndrome and toxic exposures. Table 1 highlights important causes of mononeuropathy multiplex and summarizes associated findings and indicated diagnostic tests for specific evaluation.

Another challenge for hospitalists is efficient evaluation of neuropathy. A systematic framework for creating a differential diagnosis and familiarity with available diagnostic tests is crucial. Hospitalists should be aware of three broad categories of neuropathy: mononeuropathy, polyneuropathy and mononeuropathy multiplex. Electrodiagnostic testing is essential to confirm the involved nerves and distinguishes axonal from demyelinating etiologies. Ultrasound, MR neurogram and, when indicated, nerve biopsy may be useful. Table 2 reviews these diagnostic tools as well as their indications and limitations.

Ischemic steal syndrome should be considered when neuropathy develops in a limb subsequent to arterio‐venous access procedures. Any vascular network, including the vertebral, carotid and coronary arteries, is at risk for steal. A feature common to all steal syndromes is the diversion of blood away from its original destination toward a lower pressure alternative. In some cases, this leads to a reversal of arterial flow and ischemia. Ischemic complications from AV access occur in 1‐9% of patients.1 Symptoms of steal can be mild, such as self‐limited dialysis induced pain, coldness and numbness, or severe, including severe pain, sensory and motor loss.2 If vascular compromise is sufficient, gangrene can ensue. Sensory deficits usually precede motor loss and the radial pulse is commonly absent or diminished. Other findings can include pallor of the fingers, muscle atrophy, resorption of the nail bed, and gangrene or ulcerations of the fingers. Risk factors for steal include atherosclerotic disease, female gender, age greater than 60 years, diabetes mellitus, previous surgery on the same arm, and use of the brachial artery as a donor.3 Symptoms of ischemic steal typically present within the first month after surgery, but can also be delayed; there is one report of a patient presenting one year postoperatively.4

Imaging studies such as doppler and angiography can be helpful in diagnosing ischemic steal syndrome. Fistulagrams may reveal a reversal of blood flow in the distal arm and hand, but these are reserved for cases with suspected proximal obstructive arterial disease.5 Vascular imaging studies can be misleading, however, as many patients will have physiologic but asymptomatic reversal of flow. Thus, a functional assessment such as digital plethysmography is recommended, especially in cases where clinical symptoms are vague. Digital pressures less than 60mmHg demonstrated 100% sensitivity and 87% specificity in one case control study of 40 patients.6 Treatment of ischemic steal syndrome is aimed at decreasing flow through the access shunt.

In conclusion, this case highlights the importance of timely and systematic evaluation of peripheral neuropathy in the hospital setting. Neuropathy with rapid progression and high potential for permanent damage necessitates early neurologic, or in this case, vascular consultation. Hospitalists should be facile in evaluating peripheral neuropathies and recognizing the appropriate indications for diagnostic tests and procedures.

A 60 year‐old woman with advanced kidney disease presented with one month of progressively worsening, sharp burning pain and decreased sensation in her left hand. Cold air exacerbated the pain. She noted decreasing ability to utilize her left fingers, a weakened grip and that the muscles in her hand looked smaller.

Localized sensory and motor symptoms in a discrete region of a single limb suggest neuropathy. The lack of symptoms in the face or ipsilateral lower extremity would dissuade a clinician from considering central etiologies; the presence of neuropathic pain is uncommon for cortical lesions. The involvement of motor and sensory nerves indicates peripheral nerve involvement.

The general approach to patients with peripheral neuropathy begins with identifying the neuropathy as a mononeuropathy (involving a single nerve), a polyneuropathy (symmetric involvement of multiple nerves) or a mononeuropathy multiplex (asymmetric involvement of multiple nerves). The patient, in this case, described subacute neuropathic pain, sensory loss, and weakness in her left hand in a distribution consistent with mononeuropathy or mononeuropathy multiplex.

This patient could have carpal tunnel syndrome given its prevalence in patients with advanced renal disease. The differential diagnosis is broad, however, and includes ulnar mononeuropathy, nerve ischemia due to vasculitis or vasculopathy, lower cervical radiculopathy (though the patient does not describe neck or radicular pain), lower brachial plexopathy, and complex regional pain syndrome.

The patient was diagnosed with advanced kidney disease one year ago when biopsy revealed focal segmental glomerulosclerosis secondary to lithium. Since her diagnosis, two grafts were placed in the left upper arm in anticipation of dialysis: the first, placed seven months prior to this admission, failed to mature; the second, placed one month prior to this admission, was complicated by bleeding at the fistula site and was not yet mature. Prior to this admission she had not required hemodialysis. Her past history included hypertension, dyslipidemia, hypothyroidism, secondary hyperparathyroidism, a remote history of cervical cancer (stage unknown, recent PAP smear negative), microcytosis and schizoaffective disorder. Her medications were furosemide, amlodipine, lisinopril, atenolol, atorvastatin, pantoprazole, olanzapine, levothyroxine, iron, darbepoetin, sevelamer, multivitamin and docusate.

Given the history of procedures in the left arm one should consider ischemic injury to the left median nerve. Other local complications could include compressive lesions such as an abscess or hematoma or direct nerve injury from the procedure. Carpal tunnel syndrome remains high on the differential due to its prevalence and because renal failure and hypothyroidism increase the risk of carpal tunnel syndrome.

A careful physical examination would localize the nerve or nerves involved. Examination findings that would be consistent with carpal tunnel syndrome include sensory loss in the distribution of the left median nerve, weakness of muscles innervated by the median nerve, including the abductor pollicus brevis and opponens muscles, and a Tinels and Phalens sign of the left wrist. A proximal median neuropathy resulting from ischemia or compression might also involve median‐innervated forearm muscle such as the pronator teres (forearm pronation) and flexor carpi radialis (hand flexion and abduction) muscles. Complex regional pain syndrome can be seen after a traumatic injury or surgery and is typified by severe neuropathic pain in a limb, often in combination with trophic changes in the affected extremity. A cervical radiculopathy would affect muscles supplied by the injured nerve root. For example, a C8 radiculopathy would affect all of the intrinsic hand muscles, the wrist and finger extensors, and the triceps brachii. A lower brachial plexopathy would present similarly to a lower cervical radiculopathy on clinical examination; electrodiagnostic evaluation would be necessary to distinguish these two disorders.

The patient appeared fatigued and her left hand was wrapped in blankets. Her vital signs were stable. There was no thyroid enlargement or lymphadenopathy. There was marked thenar, hypothenar and forearm atrophy on the left. Strength testing of her left hand demonstrated a grip strength of 2/5, finger extension and interosseous strength of 1/5, left wrist flexion and extension of 3/5; left biceps and triceps were 5/5. Sensation was mildly decreased to light touch, temperature, pain and proprioception throughout the left hand. Strength and sensation were intact in the right upper and bilateral lower extremities. Reflexes were 2+ throughout. The left radial pulse was diminished compared to the left ulnar that was 1+. The left hand was dry and cool. Laboratory evaluation revealed an elevated white blood cell count of 15,300/mm³, a hematocrit of 33 percent, mean corpuscular volume of 73 fL, and a normal platelet count. Electrolytes were consistent with advanced renal disease. The thyroid stimulating hormone level was normal.

The patient's examination reveals an injury to the sensory and motor components of the left ulnar, median, and distal radial nerves. The volar forearm wasting suggests proximal median motor nerve injury in the forearm. Because the triceps is spared, the weakness of finger and wrist extension implies distal radial motor nerve injury. The interosseous weakness is consistent with injury to the ulnar motor nerve. Weakness of grip and wrist flexion is less specific and it may be explained by injury to either the median or ulnar motor nerves. The diffuse sensory loss over the palmar and dorsal aspect of the left hand is consistent with neuropathic injury to the left median, ulnar, and radial sensory nerves. The preserved deep tendon reflexes are controlled by the musculocutaneous nerve (the biceps reflex) and branches arising from the proximal radial nerve (the triceps and brachioradialis reflexes), both of which are proximal to the apparent level of neuropathic insult.

Carpal tunnel syndrome is excluded since abnormalities extend beyond the median nerve distribution. The presentation is consistent with a mononeuropathy multiplex. Axonal etiologies of mononeuropathy multiplexincluding vasculitis, ischemia, neoplastic infiltration, and infectious etiologies such as Lyme diseaseare more common than demyelinating causes. Vasculitic neuropathy commonly involves the lower extremities and may have systemic symptoms, not present in this case. Neoplasm or other compressive lesions such as hematoma could explain these findings. Abscess must be considered given the leukocytosis. A lower brachial plexopathy, technically a mononeuropathy multiplex involving the proximal arm at the level of the brachial plexus, is also in the differential diagnosis. Another axonal disorder to consider would be neuralgic amyotrophy, an idiopathic form of acute brachial plexopathy associated with pain that is a complication of surgery that typically presents within a few hours to weeks of the procedure.

Demyelinating causes of mononeuropathy multiplex are less likely and include a variant of chronic inflammatory demyelinating polyneuropathy (Lewis‐Sumner syndrome) and hereditary neuropathy with liability to pressure palsies. Both processes are typically indolent and usually not painful, though the latter may present with fulminant numbness and weakness.

Nerve conduction and needle electromyography of the arm and cervical paraspinal muscles would differentiate axonal degeneration from demyelination. It would identify the affected nerves and any nerve root involvement. Given the concern for abscess or hematoma, MR neurography focused on the surgical site would also be important.

Electromyography and nerve conduction velocities demonstrated severe axonal loss of the left median, ulnar and distal radial sensory nerves consistent with acute denervation. A magnetic resonance neurogram following the course of these nerves revealed enlarged ulnar and median nerves with abnormal signal, but no compressive lesion (Fig. 1).

Figure 1

The electrodiagnostic testing is consistent with severe acute axonal injury to the left ulnar, median and radial nerves. This supports a diagnosis of mononeuropathy multiplex with axonal injury. Demyelinating causes are excluded at this point.

The MR neurogram demonstrates nonspecific nerve enlargement, which may be seen in ischemia, neoplastic processes (primary or metastatic), demyelinating disease, or, rarely, amyloidosis. Neoplastic involvement is unlikely in this case given the absence of a compressive mass lesion and the long segmental involvement of both the median and ulnar nerves. Compression from an abscess or hematoma is excluded. Neuralgic amyotrophy does not typically cause nerve enlargement.

Ischemia is the most likely diagnosis. Laboratory evaluation for vasculitis would be reasonable. Vasculitides that could present in this fashion include: polyarteritis nodosa, mixed connective tissue disease, Wegner's granulomatosis, Churg‐Strauss angiitis, Sjogren's, hepatitis C with serum cryoglobulinemia and possibly rheumatoid arthritis. Given the history of fistula placement in the affected limb, vascular sufficiency must be assessed.

Anti‐nuclear antibodies and anti‐neutrophilic cytoplasmic antibodies were negative, and a C‐ reactive protein was 5.9 mg/L (normal range, 0 to 10 mg/L). The erythrocyte sedimentation rate was 32mm/hr (normal range, 0 to 20) and serologies for hepatitis B and C were negative. There was no evidence of serum cryoglobulins.

A modestly elevated sedimentation rate and normal C‐reactive protein argue against a diagnosis of vasculitis. The negative ANA, ANCA, hepatitis serologies and cryoglobulin tests render unlikely the diagnoses of polyarteritis nodosa, Wegner's granulomatosis, Churg‐Strauss angiitis, or hepatitis related cryoglobulinemia. Eosinophilia (present in Churg‐Strauss), ENA (positive in mixed connective tissue disease), anti‐SSA and SSB (positive in Sjogren's) and a rheumatoid factor would round out this evaluation for vasculitis. A left radial sensory nerve biopsy could also be of value in diagnosing vasculitic neuropathy in this patient.

Given the evidence against vasculitis, the possibility of ischemia due to vascular insufficiency is concerning. Two ischemic complications of hemodialysis are known to cause distal multiple mononeuropathies. The first, ischemic monomelic neuropathy syndrome is seen almost exclusively in diabetics. It is characterized by the development of acute pain, weakness of the forearm and hand muscles, and sensory loss within minutes or hours of AV graft placement. Transient occlusion of the blood supply to the nerves of the forearm and hand induces nerve ischemia, but does not cause necrosis of other tissues. The nerve conduction findings in this patient are consistent with ischemic monomelic neuropathy syndrome. The delayed onset of her symptoms, however, makes this diagnosis unlikely.

The second ischemic complication of hemodialysis, and the likelier diagnosis, is vascular steal syndrome. This has a similar clinical and electrodiagnostic presentation to ischemic monomelic neuropathy syndrome, but has a latency period after surgery of days to months. Vascular steal occurs when a reversal of blood flow into the fistula steals flow from the palmar arch arteries and induces ischemia of the vasa nervorum. Vascular studies should be obtained urgently when this diagnosis is considered.

Evaluation of the arteriovenous graft and vascular surgery consultation were sought. Digital photoplethysmography revealed diminished waveforms in all fingers of the left hand. Arterial Doppler evaluation of the left upper extremity confirmed low‐velocity flow in the radial and ulnar arteries and failed to confirm flow in the brachial artery distal to the arteriovenous fistula. The patient underwent an angiogram of the left axillary and brachial arteries. There was normal flow until the level of the arteriovenous fistula but minimal flow distal to the fistula (Fig. 2).

Figure 2

The diminished waveforms on digital photoplethysmography are consistent with poor perfusion distally. The angiogram suggests that the multiple mononeuropathies are a consequence of ischemia from impaired blood flow.

Consulting the vascular surgeons in this setting is essential because restoring adequate blood flow to the affected nerves can prevent further loss of function. Prognosis is dependent on many factors, including the severity of the functional loss and the duration of the symptoms prior to the restoration of blood flow. The patient's severe weakness and substantial muscle atrophy, manifestations of axonal degeneration, imply a poorer prognosis for recovery of function.

Embolization of the arteriovenous fistula was performed by interventional radiology. Post embolization angiograms demonstrated improved peripheral arterial flow (Fig. 3). One day later, the patient's finger flexion and extension improved. She reported mildly decreased dysesthesias and on examination her fingers were warmer to the touch. One month after discharge, her strength continued to be impaired, though improved and she still experienced pain.

Figure 3

COMMENTARY

Hospitalists must be equipped to recognize urgent and potentially reversible causes of neuropathy. The hospitalist should maintain a high index of suspicion for ischemia (either due to vasculitis or vascular compromise), traumatic nerve injury, nerve compression or entrapment, lymphoma or metastatic infiltration, hepatitis C with cryoglobulinemia, Guillain‐Barre syndrome and toxic exposures. Table 1 highlights important causes of mononeuropathy multiplex and summarizes associated findings and indicated diagnostic tests for specific evaluation.

Another challenge for hospitalists is efficient evaluation of neuropathy. A systematic framework for creating a differential diagnosis and familiarity with available diagnostic tests is crucial. Hospitalists should be aware of three broad categories of neuropathy: mononeuropathy, polyneuropathy and mononeuropathy multiplex. Electrodiagnostic testing is essential to confirm the involved nerves and distinguishes axonal from demyelinating etiologies. Ultrasound, MR neurogram and, when indicated, nerve biopsy may be useful. Table 2 reviews these diagnostic tools as well as their indications and limitations.

Ischemic steal syndrome should be considered when neuropathy develops in a limb subsequent to arterio‐venous access procedures. Any vascular network, including the vertebral, carotid and coronary arteries, is at risk for steal. A feature common to all steal syndromes is the diversion of blood away from its original destination toward a lower pressure alternative. In some cases, this leads to a reversal of arterial flow and ischemia. Ischemic complications from AV access occur in 1‐9% of patients.1 Symptoms of steal can be mild, such as self‐limited dialysis induced pain, coldness and numbness, or severe, including severe pain, sensory and motor loss.2 If vascular compromise is sufficient, gangrene can ensue. Sensory deficits usually precede motor loss and the radial pulse is commonly absent or diminished. Other findings can include pallor of the fingers, muscle atrophy, resorption of the nail bed, and gangrene or ulcerations of the fingers. Risk factors for steal include atherosclerotic disease, female gender, age greater than 60 years, diabetes mellitus, previous surgery on the same arm, and use of the brachial artery as a donor.3 Symptoms of ischemic steal typically present within the first month after surgery, but can also be delayed; there is one report of a patient presenting one year postoperatively.4

Imaging studies such as doppler and angiography can be helpful in diagnosing ischemic steal syndrome. Fistulagrams may reveal a reversal of blood flow in the distal arm and hand, but these are reserved for cases with suspected proximal obstructive arterial disease.5 Vascular imaging studies can be misleading, however, as many patients will have physiologic but asymptomatic reversal of flow. Thus, a functional assessment such as digital plethysmography is recommended, especially in cases where clinical symptoms are vague. Digital pressures less than 60mmHg demonstrated 100% sensitivity and 87% specificity in one case control study of 40 patients.6 Treatment of ischemic steal syndrome is aimed at decreasing flow through the access shunt.

In conclusion, this case highlights the importance of timely and systematic evaluation of peripheral neuropathy in the hospital setting. Neuropathy with rapid progression and high potential for permanent damage necessitates early neurologic, or in this case, vascular consultation. Hospitalists should be facile in evaluating peripheral neuropathies and recognizing the appropriate indications for diagnostic tests and procedures.

A 60 year‐old woman with advanced kidney disease presented with one month of progressively worsening, sharp burning pain and decreased sensation in her left hand. Cold air exacerbated the pain. She noted decreasing ability to utilize her left fingers, a weakened grip and that the muscles in her hand looked smaller.

Localized sensory and motor symptoms in a discrete region of a single limb suggest neuropathy. The lack of symptoms in the face or ipsilateral lower extremity would dissuade a clinician from considering central etiologies; the presence of neuropathic pain is uncommon for cortical lesions. The involvement of motor and sensory nerves indicates peripheral nerve involvement.

The general approach to patients with peripheral neuropathy begins with identifying the neuropathy as a mononeuropathy (involving a single nerve), a polyneuropathy (symmetric involvement of multiple nerves) or a mononeuropathy multiplex (asymmetric involvement of multiple nerves). The patient, in this case, described subacute neuropathic pain, sensory loss, and weakness in her left hand in a distribution consistent with mononeuropathy or mononeuropathy multiplex.

This patient could have carpal tunnel syndrome given its prevalence in patients with advanced renal disease. The differential diagnosis is broad, however, and includes ulnar mononeuropathy, nerve ischemia due to vasculitis or vasculopathy, lower cervical radiculopathy (though the patient does not describe neck or radicular pain), lower brachial plexopathy, and complex regional pain syndrome.

The patient was diagnosed with advanced kidney disease one year ago when biopsy revealed focal segmental glomerulosclerosis secondary to lithium. Since her diagnosis, two grafts were placed in the left upper arm in anticipation of dialysis: the first, placed seven months prior to this admission, failed to mature; the second, placed one month prior to this admission, was complicated by bleeding at the fistula site and was not yet mature. Prior to this admission she had not required hemodialysis. Her past history included hypertension, dyslipidemia, hypothyroidism, secondary hyperparathyroidism, a remote history of cervical cancer (stage unknown, recent PAP smear negative), microcytosis and schizoaffective disorder. Her medications were furosemide, amlodipine, lisinopril, atenolol, atorvastatin, pantoprazole, olanzapine, levothyroxine, iron, darbepoetin, sevelamer, multivitamin and docusate.

Given the history of procedures in the left arm one should consider ischemic injury to the left median nerve. Other local complications could include compressive lesions such as an abscess or hematoma or direct nerve injury from the procedure. Carpal tunnel syndrome remains high on the differential due to its prevalence and because renal failure and hypothyroidism increase the risk of carpal tunnel syndrome.

A careful physical examination would localize the nerve or nerves involved. Examination findings that would be consistent with carpal tunnel syndrome include sensory loss in the distribution of the left median nerve, weakness of muscles innervated by the median nerve, including the abductor pollicus brevis and opponens muscles, and a Tinels and Phalens sign of the left wrist. A proximal median neuropathy resulting from ischemia or compression might also involve median‐innervated forearm muscle such as the pronator teres (forearm pronation) and flexor carpi radialis (hand flexion and abduction) muscles. Complex regional pain syndrome can be seen after a traumatic injury or surgery and is typified by severe neuropathic pain in a limb, often in combination with trophic changes in the affected extremity. A cervical radiculopathy would affect muscles supplied by the injured nerve root. For example, a C8 radiculopathy would affect all of the intrinsic hand muscles, the wrist and finger extensors, and the triceps brachii. A lower brachial plexopathy would present similarly to a lower cervical radiculopathy on clinical examination; electrodiagnostic evaluation would be necessary to distinguish these two disorders.

The patient appeared fatigued and her left hand was wrapped in blankets. Her vital signs were stable. There was no thyroid enlargement or lymphadenopathy. There was marked thenar, hypothenar and forearm atrophy on the left. Strength testing of her left hand demonstrated a grip strength of 2/5, finger extension and interosseous strength of 1/5, left wrist flexion and extension of 3/5; left biceps and triceps were 5/5. Sensation was mildly decreased to light touch, temperature, pain and proprioception throughout the left hand. Strength and sensation were intact in the right upper and bilateral lower extremities. Reflexes were 2+ throughout. The left radial pulse was diminished compared to the left ulnar that was 1+. The left hand was dry and cool. Laboratory evaluation revealed an elevated white blood cell count of 15,300/mm³, a hematocrit of 33 percent, mean corpuscular volume of 73 fL, and a normal platelet count. Electrolytes were consistent with advanced renal disease. The thyroid stimulating hormone level was normal.

The patient's examination reveals an injury to the sensory and motor components of the left ulnar, median, and distal radial nerves. The volar forearm wasting suggests proximal median motor nerve injury in the forearm. Because the triceps is spared, the weakness of finger and wrist extension implies distal radial motor nerve injury. The interosseous weakness is consistent with injury to the ulnar motor nerve. Weakness of grip and wrist flexion is less specific and it may be explained by injury to either the median or ulnar motor nerves. The diffuse sensory loss over the palmar and dorsal aspect of the left hand is consistent with neuropathic injury to the left median, ulnar, and radial sensory nerves. The preserved deep tendon reflexes are controlled by the musculocutaneous nerve (the biceps reflex) and branches arising from the proximal radial nerve (the triceps and brachioradialis reflexes), both of which are proximal to the apparent level of neuropathic insult.

Carpal tunnel syndrome is excluded since abnormalities extend beyond the median nerve distribution. The presentation is consistent with a mononeuropathy multiplex. Axonal etiologies of mononeuropathy multiplexincluding vasculitis, ischemia, neoplastic infiltration, and infectious etiologies such as Lyme diseaseare more common than demyelinating causes. Vasculitic neuropathy commonly involves the lower extremities and may have systemic symptoms, not present in this case. Neoplasm or other compressive lesions such as hematoma could explain these findings. Abscess must be considered given the leukocytosis. A lower brachial plexopathy, technically a mononeuropathy multiplex involving the proximal arm at the level of the brachial plexus, is also in the differential diagnosis. Another axonal disorder to consider would be neuralgic amyotrophy, an idiopathic form of acute brachial plexopathy associated with pain that is a complication of surgery that typically presents within a few hours to weeks of the procedure.

Demyelinating causes of mononeuropathy multiplex are less likely and include a variant of chronic inflammatory demyelinating polyneuropathy (Lewis‐Sumner syndrome) and hereditary neuropathy with liability to pressure palsies. Both processes are typically indolent and usually not painful, though the latter may present with fulminant numbness and weakness.

Nerve conduction and needle electromyography of the arm and cervical paraspinal muscles would differentiate axonal degeneration from demyelination. It would identify the affected nerves and any nerve root involvement. Given the concern for abscess or hematoma, MR neurography focused on the surgical site would also be important.

Electromyography and nerve conduction velocities demonstrated severe axonal loss of the left median, ulnar and distal radial sensory nerves consistent with acute denervation. A magnetic resonance neurogram following the course of these nerves revealed enlarged ulnar and median nerves with abnormal signal, but no compressive lesion (Fig. 1).

Figure 1

The electrodiagnostic testing is consistent with severe acute axonal injury to the left ulnar, median and radial nerves. This supports a diagnosis of mononeuropathy multiplex with axonal injury. Demyelinating causes are excluded at this point.

The MR neurogram demonstrates nonspecific nerve enlargement, which may be seen in ischemia, neoplastic processes (primary or metastatic), demyelinating disease, or, rarely, amyloidosis. Neoplastic involvement is unlikely in this case given the absence of a compressive mass lesion and the long segmental involvement of both the median and ulnar nerves. Compression from an abscess or hematoma is excluded. Neuralgic amyotrophy does not typically cause nerve enlargement.

Ischemia is the most likely diagnosis. Laboratory evaluation for vasculitis would be reasonable. Vasculitides that could present in this fashion include: polyarteritis nodosa, mixed connective tissue disease, Wegner's granulomatosis, Churg‐Strauss angiitis, Sjogren's, hepatitis C with serum cryoglobulinemia and possibly rheumatoid arthritis. Given the history of fistula placement in the affected limb, vascular sufficiency must be assessed.

Anti‐nuclear antibodies and anti‐neutrophilic cytoplasmic antibodies were negative, and a C‐ reactive protein was 5.9 mg/L (normal range, 0 to 10 mg/L). The erythrocyte sedimentation rate was 32mm/hr (normal range, 0 to 20) and serologies for hepatitis B and C were negative. There was no evidence of serum cryoglobulins.

A modestly elevated sedimentation rate and normal C‐reactive protein argue against a diagnosis of vasculitis. The negative ANA, ANCA, hepatitis serologies and cryoglobulin tests render unlikely the diagnoses of polyarteritis nodosa, Wegner's granulomatosis, Churg‐Strauss angiitis, or hepatitis related cryoglobulinemia. Eosinophilia (present in Churg‐Strauss), ENA (positive in mixed connective tissue disease), anti‐SSA and SSB (positive in Sjogren's) and a rheumatoid factor would round out this evaluation for vasculitis. A left radial sensory nerve biopsy could also be of value in diagnosing vasculitic neuropathy in this patient.

Given the evidence against vasculitis, the possibility of ischemia due to vascular insufficiency is concerning. Two ischemic complications of hemodialysis are known to cause distal multiple mononeuropathies. The first, ischemic monomelic neuropathy syndrome is seen almost exclusively in diabetics. It is characterized by the development of acute pain, weakness of the forearm and hand muscles, and sensory loss within minutes or hours of AV graft placement. Transient occlusion of the blood supply to the nerves of the forearm and hand induces nerve ischemia, but does not cause necrosis of other tissues. The nerve conduction findings in this patient are consistent with ischemic monomelic neuropathy syndrome. The delayed onset of her symptoms, however, makes this diagnosis unlikely.

The second ischemic complication of hemodialysis, and the likelier diagnosis, is vascular steal syndrome. This has a similar clinical and electrodiagnostic presentation to ischemic monomelic neuropathy syndrome, but has a latency period after surgery of days to months. Vascular steal occurs when a reversal of blood flow into the fistula steals flow from the palmar arch arteries and induces ischemia of the vasa nervorum. Vascular studies should be obtained urgently when this diagnosis is considered.

Evaluation of the arteriovenous graft and vascular surgery consultation were sought. Digital photoplethysmography revealed diminished waveforms in all fingers of the left hand. Arterial Doppler evaluation of the left upper extremity confirmed low‐velocity flow in the radial and ulnar arteries and failed to confirm flow in the brachial artery distal to the arteriovenous fistula. The patient underwent an angiogram of the left axillary and brachial arteries. There was normal flow until the level of the arteriovenous fistula but minimal flow distal to the fistula (Fig. 2).

Figure 2

The diminished waveforms on digital photoplethysmography are consistent with poor perfusion distally. The angiogram suggests that the multiple mononeuropathies are a consequence of ischemia from impaired blood flow.

Consulting the vascular surgeons in this setting is essential because restoring adequate blood flow to the affected nerves can prevent further loss of function. Prognosis is dependent on many factors, including the severity of the functional loss and the duration of the symptoms prior to the restoration of blood flow. The patient's severe weakness and substantial muscle atrophy, manifestations of axonal degeneration, imply a poorer prognosis for recovery of function.

Embolization of the arteriovenous fistula was performed by interventional radiology. Post embolization angiograms demonstrated improved peripheral arterial flow (Fig. 3). One day later, the patient's finger flexion and extension improved. She reported mildly decreased dysesthesias and on examination her fingers were warmer to the touch. One month after discharge, her strength continued to be impaired, though improved and she still experienced pain.

Figure 3

COMMENTARY

Hospitalists must be equipped to recognize urgent and potentially reversible causes of neuropathy. The hospitalist should maintain a high index of suspicion for ischemia (either due to vasculitis or vascular compromise), traumatic nerve injury, nerve compression or entrapment, lymphoma or metastatic infiltration, hepatitis C with cryoglobulinemia, Guillain‐Barre syndrome and toxic exposures. Table 1 highlights important causes of mononeuropathy multiplex and summarizes associated findings and indicated diagnostic tests for specific evaluation.

Another challenge for hospitalists is efficient evaluation of neuropathy. A systematic framework for creating a differential diagnosis and familiarity with available diagnostic tests is crucial. Hospitalists should be aware of three broad categories of neuropathy: mononeuropathy, polyneuropathy and mononeuropathy multiplex. Electrodiagnostic testing is essential to confirm the involved nerves and distinguishes axonal from demyelinating etiologies. Ultrasound, MR neurogram and, when indicated, nerve biopsy may be useful. Table 2 reviews these diagnostic tools as well as their indications and limitations.

Ischemic steal syndrome should be considered when neuropathy develops in a limb subsequent to arterio‐venous access procedures. Any vascular network, including the vertebral, carotid and coronary arteries, is at risk for steal. A feature common to all steal syndromes is the diversion of blood away from its original destination toward a lower pressure alternative. In some cases, this leads to a reversal of arterial flow and ischemia. Ischemic complications from AV access occur in 1‐9% of patients.1 Symptoms of steal can be mild, such as self‐limited dialysis induced pain, coldness and numbness, or severe, including severe pain, sensory and motor loss.2 If vascular compromise is sufficient, gangrene can ensue. Sensory deficits usually precede motor loss and the radial pulse is commonly absent or diminished. Other findings can include pallor of the fingers, muscle atrophy, resorption of the nail bed, and gangrene or ulcerations of the fingers. Risk factors for steal include atherosclerotic disease, female gender, age greater than 60 years, diabetes mellitus, previous surgery on the same arm, and use of the brachial artery as a donor.3 Symptoms of ischemic steal typically present within the first month after surgery, but can also be delayed; there is one report of a patient presenting one year postoperatively.4

Imaging studies such as doppler and angiography can be helpful in diagnosing ischemic steal syndrome. Fistulagrams may reveal a reversal of blood flow in the distal arm and hand, but these are reserved for cases with suspected proximal obstructive arterial disease.5 Vascular imaging studies can be misleading, however, as many patients will have physiologic but asymptomatic reversal of flow. Thus, a functional assessment such as digital plethysmography is recommended, especially in cases where clinical symptoms are vague. Digital pressures less than 60mmHg demonstrated 100% sensitivity and 87% specificity in one case control study of 40 patients.6 Treatment of ischemic steal syndrome is aimed at decreasing flow through the access shunt.

In conclusion, this case highlights the importance of timely and systematic evaluation of peripheral neuropathy in the hospital setting. Neuropathy with rapid progression and high potential for permanent damage necessitates early neurologic, or in this case, vascular consultation. Hospitalists should be facile in evaluating peripheral neuropathies and recognizing the appropriate indications for diagnostic tests and procedures.

A 26‐year‐old woman was brought to the emergency department following several episodes of seizures. The patient's friend witnessed several 15‐minute episodes of sudden jerks and tremors of her right arm during which the patient bit her tongue, had word‐finding difficulty, had horizontal eye deviation, and was incontinent of urine. She became unresponsive during the episodes, with incomplete recovery of consciousness between attacks. She was afebrile. Her neurologic exam 4 hours after several seizures revealed word‐finding difficulty and right arm weakness. A complete blood count, chemistry panel including renal and liver function tests, urine toxicology screen, and computed tomography (CT) of the head were normal. After a loading dose of fosphenytoin, the patient did not experience further seizures and was discharged on a maintenance dose of phenytoin.

Over the next week, the patient continued to note a sensation of heaviness in her right arm and felt fatigued. The patient's mother brought her back to the emergency department after witnessing a similar seizure episode that persisted for an hour. On arrival, the patient was no longer seizing.

Although it can sometimes be difficult to differentiate between seizure, stroke, syncope, and other causes of transient loss of consciousness, this constellation of symptoms strongly points to a seizure. I would classify the patient's focal arm movements associated with impaired consciousness as partial complex seizures. One of the first considerations is determining whether the seizure is caused by a systemic process or by an intrinsic central nervous system disorder. Common systemic illnesses include infections, metabolic disturbances, toxins, and malignancies, none of which are evident on the preliminary evaluation. The absence of fever is important as is the time frame (now extending over 1 week) in excluding acute bacterial meningitis. A negative urine toxicology is very helpful but does not exclude the possibility that the seizure is from unmeasured drug intoxication, for example, tricyclic antidepressants, or from drug withdrawal, for example, benzodiazepines, barbiturates, ethanol, and antiepileptic drugs. The persistent right arm heaviness and right arm jerking during the seizures suggest a left cortical focus that the CT scan did not detect. Without a clear diagnosis and with recurrent seizures despite antiepileptic drugs, hospitalization is warranted.

The patient experienced migraine headaches each month during menses. There was no family history of seizures. Her only medication was phenytoin. The mother was unaware of any use of tobacco, alcohol, or recreational drugs. The patient was raised in New Jersey and moved to the San Francisco Bay area 9 months ago. She had no pets and had traveled to Florida and Montreal in the past 6 months. She was a graduate student in performing arts. During the preceding 2 weeks she had been under significant stress and had not slept much in preparation for an upcoming production. The patient's mother was not aware of any head trauma, recent illness, fevers, chills, weight loss, photosensitivity, arthralgias, nausea, vomiting, or diarrhea.

Recent sleep deprivation could provoke seizures in a patient with a latent anatomic focus or metabolic predisposition. Nonadherence to antiepileptic drug therapy is the most common reason for patients to present to the ED with seizures; therefore, I would check a phenytoin level to assess whether she is at a therapeutic level and would consider administering another loading dose. In the absence of immunocompromise or unusual activities or exposures, North American travel does not bring to mind additional etiologies at this time.

On exam, temperature was 37.3C, blood pressure was 148/84 mm Hg, heart rate was 120 per minute, and respiratory rate was 16 per minute. The patient was stuporous and withdrew from painful stimuli. She was unable to speak. Pupils were 4 mm in diameter and reacted to light. No gaze preference or nystagmus was present. There was no meningismus. Deep tendon reflexes were 1+ and symmetrical in both upper and lower extremities. Plantar reflexes were extensor bilaterally. The tone in the right upper extremity was mildly increased compared to the left. The patient demonstrated semipurposeful movement of the limbs, such as reaching for the bed rails with her arms. Examination of the heart, lungs, abdomen, skin, and oropharynx was normal.

The white blood cell count was 22,300/mm³ with 50% neutrophils, 40% lymphocytes, 7% monocytes, and 3% eosinophils. Results of the chemistry panel including electrolytes, glucose, creatinine, and liver enzymes, urinalysis, and thyroid‐stimulating hormone were normal. Serum phenytoin level was 8.1 g/mL. Urine toxicology screen, obtained after the patient had received lorazepam, was positive only for benzodiazepines. A chest radiograph was normal.

The cerebrospinal fluid (CSF) was colorless, containing 35 white blood cells/mm³ (48% lymphocytes, 30% neutrophils, 22% monocytes), 3 red blood cells/mm³, 62 mg/dL protein, and 50 mg/dL glucose. There was no xanthochromia. The CSF was negative for cryptococcal antigen, antibodies to West Nile virus, PCR for herpes simplex viruses‐1 and ‐2, and PCR for Borrelia burgdorferi. CSF bacterial culture, cryptococcal antigen, and AFB stain were negative. The serum antinuclear antibody, rheumatoid factor, and rapid plasma reagin were negative. Serum antibodies to human immunodeficiency virus, hepatitis B and C viruses, Borrelia burgdorferi, and herpes simplex viruses were negative. The erythrocyte sedimentation rate was 25 mm/hr. There was no growth in her blood cultures.

These CSF findings have to be interpreted in light of her clinical picture, as they are congruent with both an aseptic meningitis and encephalitis. In practice, these can be hard to distinguish, but the early and dominant cortical findings (focal neurologic deficits, prominent altered mental status, bilateral extensor plantar reflexes) and absence of meningeal signs favor encephalitis. This CSF profile can be seen in a variety of disease processes causing a meningoencephalitis, including partially treated bacterial meningitis; meningitis due to viruses, fungi, mycobacteria, or atypical bacteria (eg, Listeria); neurosarcoidosis; carcinomatous meningitis; and infection or inflammation from a parameningeal focus in the sinuses, epidural space, or brain parenchyma. Seizure itself can lead to a postictal pleocytosis in the CSF, although this degree of inflammation would be unusual. Many tests can be sent, and the clinicians appropriately focused on some of the most treatable and serious etiologies first. The negative HIV test limits the list of opportunistic pathogens. The negative ANA substantially lowers the likelihood of systemic lupus, an important consideration in a young woman with an inflammatory disorder involving the central nervous system.

Magnetic resonance imaging (MRI) of the brain showed cortical T2 prolongation with significant enhancement with gadolinium in the cortex and leptomeninges of the left parietal and posterotemporal lobes and right cingulate gyrus region (Fig. 1). The patient was admitted to the intensive care unit, and phenytoin and levetiracetam were administered. Over the next several days, she remained afebrile, and her leukocytosis resolved. She continued to have seizures every day despite receiving phenytoin, levetiracetam, and lamotrigine. She was alert and complained about persistent right arm weakness and word‐finding difficulties. Posterior cervical lymphadenopathy at the base of her left occiput was detected on subsequent exam.

Figure 1

An excisional lymph node biopsy demonstrated extensive necrosis without evidence of granulomata, malignancy, or lymphoproliferative disease. Stains and cultures for bacteria, fungi, and mycobacteria were negative. The patient's electroencephalogram captured epileptiform activity over the left hemisphere 2 hours after a cluster of seizures. MR angiography and cerebral angiography demonstrated no abnormalities.

Despite this additional information, there is no distinguishing clue that points to a single diagnosis. This is a 26‐year‐old healthy, seemingly immunocompetent woman who has had a 2‐week progressive and refractory seizure disorder secondary to a multifocal neuroinvasive process with a CSF pleocytosis. She does not have evidence of a systemic underlying disorder, save for nonspecific localized lymphadenopathy and a transient episode of leukocytosis on admission, and has no distinguishing epidemiological factors or exposures.

Despite my initial concerns for infectious meningoencephalitis, the negative stains, serologies, and cultures of the blood, CSF, and lymph nodes in the setting of a normal immune system and no suspect exposure substantially lower this probability. Arthropod‐borne viruses are still possible, especially West Nile virus, because the serological tests are less sensitive early in the illness, acknowledging that the absence of fever, weakness, and known mosquito bites detracts from this diagnosis. Pathogens that cause regional lymphadenopathy and encephalitis such as Bartonella remain possibilities, as the history of exposure to a kitten can be easily overlooked.

Rheumatologic disorders merit close attention in a young woman, but the negative ANA makes lupus cerebritis unlikely, and the 2 angiograms did not detect evidence of vasculitis. Finally, there is the question of malignancy and other miscellaneous infiltrative disorders (such as sarcoid), which are of importance here because of the multifocal cortical involvement on imaging.

At this point, I would resample the CSF for viral etiologies (eg, West Nile virus) and cytology and would send serum Bartonella serologies. If these studies were negative, a brain biopsy, primarily to exclude malignancy but also to uncover an unsuspected process, would be indicated. I cannot make a definitive diagnosis or find a perfect fit here, but in the absence of strong evidence of an infection, I am concerned about a malignancy, perhaps a low‐grade primary brain tumor.

Brain biopsy of the leptomeninges and cortex of the left parietal lobe showed multiple blood vessels infiltrated by lymphocytes, neutrophils, and eosinophils (Fig. 2). The pattern of inflammation was consistent with primary angiitis of the central nervous system (PACNS). The patient received 1 g of intravenous methylprednisolone on 3 consecutive days, followed by oral prednisone and cyclophosphamide. The seizures ceased, and she made steady progress with rehabilitation therapy. Four months after discharge a cerebral angiogram (done to ensure there was no interval evidence of vasculitis prior to tapering therapy) demonstrated patency of all major intracranial arteries and venous sinuses.

Figure 2

COMMENTARY

When a patient presents with symptoms or signs referable to the central nervous system (CNS), hospitalists must simultaneously consider primary neurologic disorders and systemic diseases that involve the CNS. Initial evaluation includes a thorough history and physical examination, basic lab studies, routine CSF analysis, and neuroimaging (often a CT scan of the head). Complicated neurologic cases may warrant more elaborate testing including EEG, brain MRI, cerebral angiography, and specialized blood and CSF studies. Clinicians may still find themselves faced with a patient who has clear CNS dysfunction but no obvious diagnosis despite an exhaustive and expensive evaluation. Several disorders match this profile including intravascular lymphoma, prion diseases, paraneoplastic syndromes, and cerebritis. Primary angiitis of the central nervous system (PACNS), a rare disorder characterized by inflammation of the medium‐sized and small arteries of the CNS, is among these disorders. Although the aforementioned diseases may sometimes have suggestive or even pathognomonic features (eg, the string of beads angiographic appearance in vasculitides), they are challenging to diagnose when such findings are absent.

Like any vasculitis of the CNS, PACNS may present with a wide spectrum of clinical features.12 Although headache and altered mental status are the most common complaints, paresis, seizures, ataxia, visual changes, and aphasia have all been described. The onset of symptoms ranges from acute to chronic, and neurologic deficits can be focal or diffuse. Systemic manifestations such as fever and weight loss are rare. The average age of onset is 42 years, with no significant sex preponderance. The histopathology of PACNS is granulomatous inflammation of arteries in the parenchyma and leptomeninges of the brain and less commonly in the spinal cord. The narrowing of the affected vessels causes cerebral ischemia and the associated neurologic deficits. The trigger for this focal inflammation is unknown.

After common disorders have been excluded in cases of CNS dysfunction, compatible CSF findings and imaging results may prompt consideration of PACNS. CSF analysis in patients with PACNS typically demonstrates a lymphocytic pleocytosis. MRI abnormalities in PACNS include multiple infarcts in the cortex, deep white matter, or leptomeninges.34 Less specific findings are contrast enhancement in the leptomeninges and white matter disease, both of which may direct the site for meningeal and brain biopsy.

Both brain MRA and cerebral angiography have a limited role in the diagnosis of vasculitis within the CNS. In 18 patients with CNS vasculitis due to autoimmune disease, all had parenchymal abnormalities on MRA but only 65% had evidence of vasculitis on angiography. In 2 retrospective studies of patients with suspected PACNS, abnormal angiograms had a specificity less than 30% for PACNS, whereas brain biopsies had a negative predictive value of 70%.57 Although in practice patients with compatible clinical features are sometimes diagnosed with CNS vasculitis on the basis of angiographic findings, brain biopsy is necessary to differentiate vasculitis from other vasculopathies and to establish a definitive diagnosis.

Before a diagnosis of PACNS is made, care must be taken to exclude infections, neoplasms, and autoimmune processes that cause angiitis of the CNS (Table 1). The presence of any extracranial abnormalities (which were not present in this case) should prompt consideration of an underlying systemic disorder causing a secondary CNS vasculitis and should cast doubt on the diagnosis of PACNS. Meningovascular syphilis and tuberculosis are among the long list of infections that may cause inflammation of the CNS vasculature. Autoimmune disorders that may cause vasculitis inside the brain include polyarteritis nodosa and Wegener's granulomatosis. Reversible cerebral vasoconstrictive disease, which is most commonly seen in women ages 20 to 50, and sympathomimetic toxins such as cocaine and amphetamine may exhibit clinical and angiographic abnormalities indistinguishable from PACNS.89

There are no prospective trials investigating PACNS treatment. Aggressive immunosuppression with cyclophosphamide and glucocorticoids is the mainstay of treatment. The duration of treatment varies with the severity of the disease and response to therapy. One study suggests that treatment should be continued for 6 to 12 months.10 Neurologic deficits may remain irreversible because of scarring of the affected vessels. Serial brain MRI examinations are often used to follow radiographic resolution during and after the therapy, although radiographic changes do not predict clinical response.11 New abnormalities on MRI, however, delay any tapering of treatment. The availability of neuroimaging studies and immunosuppressive therapy has improved the prognosis of PACNS. One study reported a favorable outcome with a 29% relapse rate and a 10% mortality rate in 54 patients over a mean follow‐up period of 35 months.12

PACNS remains a challenging diagnosis because of its rarity, the wide range of neurologic manifestations, and the difficulty in establishing a diagnosis noninvasively. It is an extremely uncommon disease but should be considered in patients with unexplained neurologic deficits referable to the CNS alone after an exhaustive workup. Ultimately, the diagnosis is made by a thorough history and physical examination, exclusion of underlying conditions (particularly systemic vasculitides and infections), and histological confirmation.

A 26‐year‐old woman was brought to the emergency department following several episodes of seizures. The patient's friend witnessed several 15‐minute episodes of sudden jerks and tremors of her right arm during which the patient bit her tongue, had word‐finding difficulty, had horizontal eye deviation, and was incontinent of urine. She became unresponsive during the episodes, with incomplete recovery of consciousness between attacks. She was afebrile. Her neurologic exam 4 hours after several seizures revealed word‐finding difficulty and right arm weakness. A complete blood count, chemistry panel including renal and liver function tests, urine toxicology screen, and computed tomography (CT) of the head were normal. After a loading dose of fosphenytoin, the patient did not experience further seizures and was discharged on a maintenance dose of phenytoin.

Over the next week, the patient continued to note a sensation of heaviness in her right arm and felt fatigued. The patient's mother brought her back to the emergency department after witnessing a similar seizure episode that persisted for an hour. On arrival, the patient was no longer seizing.

Although it can sometimes be difficult to differentiate between seizure, stroke, syncope, and other causes of transient loss of consciousness, this constellation of symptoms strongly points to a seizure. I would classify the patient's focal arm movements associated with impaired consciousness as partial complex seizures. One of the first considerations is determining whether the seizure is caused by a systemic process or by an intrinsic central nervous system disorder. Common systemic illnesses include infections, metabolic disturbances, toxins, and malignancies, none of which are evident on the preliminary evaluation. The absence of fever is important as is the time frame (now extending over 1 week) in excluding acute bacterial meningitis. A negative urine toxicology is very helpful but does not exclude the possibility that the seizure is from unmeasured drug intoxication, for example, tricyclic antidepressants, or from drug withdrawal, for example, benzodiazepines, barbiturates, ethanol, and antiepileptic drugs. The persistent right arm heaviness and right arm jerking during the seizures suggest a left cortical focus that the CT scan did not detect. Without a clear diagnosis and with recurrent seizures despite antiepileptic drugs, hospitalization is warranted.

The patient experienced migraine headaches each month during menses. There was no family history of seizures. Her only medication was phenytoin. The mother was unaware of any use of tobacco, alcohol, or recreational drugs. The patient was raised in New Jersey and moved to the San Francisco Bay area 9 months ago. She had no pets and had traveled to Florida and Montreal in the past 6 months. She was a graduate student in performing arts. During the preceding 2 weeks she had been under significant stress and had not slept much in preparation for an upcoming production. The patient's mother was not aware of any head trauma, recent illness, fevers, chills, weight loss, photosensitivity, arthralgias, nausea, vomiting, or diarrhea.

Recent sleep deprivation could provoke seizures in a patient with a latent anatomic focus or metabolic predisposition. Nonadherence to antiepileptic drug therapy is the most common reason for patients to present to the ED with seizures; therefore, I would check a phenytoin level to assess whether she is at a therapeutic level and would consider administering another loading dose. In the absence of immunocompromise or unusual activities or exposures, North American travel does not bring to mind additional etiologies at this time.

On exam, temperature was 37.3C, blood pressure was 148/84 mm Hg, heart rate was 120 per minute, and respiratory rate was 16 per minute. The patient was stuporous and withdrew from painful stimuli. She was unable to speak. Pupils were 4 mm in diameter and reacted to light. No gaze preference or nystagmus was present. There was no meningismus. Deep tendon reflexes were 1+ and symmetrical in both upper and lower extremities. Plantar reflexes were extensor bilaterally. The tone in the right upper extremity was mildly increased compared to the left. The patient demonstrated semipurposeful movement of the limbs, such as reaching for the bed rails with her arms. Examination of the heart, lungs, abdomen, skin, and oropharynx was normal.

The white blood cell count was 22,300/mm³ with 50% neutrophils, 40% lymphocytes, 7% monocytes, and 3% eosinophils. Results of the chemistry panel including electrolytes, glucose, creatinine, and liver enzymes, urinalysis, and thyroid‐stimulating hormone were normal. Serum phenytoin level was 8.1 g/mL. Urine toxicology screen, obtained after the patient had received lorazepam, was positive only for benzodiazepines. A chest radiograph was normal.

The cerebrospinal fluid (CSF) was colorless, containing 35 white blood cells/mm³ (48% lymphocytes, 30% neutrophils, 22% monocytes), 3 red blood cells/mm³, 62 mg/dL protein, and 50 mg/dL glucose. There was no xanthochromia. The CSF was negative for cryptococcal antigen, antibodies to West Nile virus, PCR for herpes simplex viruses‐1 and ‐2, and PCR for Borrelia burgdorferi. CSF bacterial culture, cryptococcal antigen, and AFB stain were negative. The serum antinuclear antibody, rheumatoid factor, and rapid plasma reagin were negative. Serum antibodies to human immunodeficiency virus, hepatitis B and C viruses, Borrelia burgdorferi, and herpes simplex viruses were negative. The erythrocyte sedimentation rate was 25 mm/hr. There was no growth in her blood cultures.

These CSF findings have to be interpreted in light of her clinical picture, as they are congruent with both an aseptic meningitis and encephalitis. In practice, these can be hard to distinguish, but the early and dominant cortical findings (focal neurologic deficits, prominent altered mental status, bilateral extensor plantar reflexes) and absence of meningeal signs favor encephalitis. This CSF profile can be seen in a variety of disease processes causing a meningoencephalitis, including partially treated bacterial meningitis; meningitis due to viruses, fungi, mycobacteria, or atypical bacteria (eg, Listeria); neurosarcoidosis; carcinomatous meningitis; and infection or inflammation from a parameningeal focus in the sinuses, epidural space, or brain parenchyma. Seizure itself can lead to a postictal pleocytosis in the CSF, although this degree of inflammation would be unusual. Many tests can be sent, and the clinicians appropriately focused on some of the most treatable and serious etiologies first. The negative HIV test limits the list of opportunistic pathogens. The negative ANA substantially lowers the likelihood of systemic lupus, an important consideration in a young woman with an inflammatory disorder involving the central nervous system.

Magnetic resonance imaging (MRI) of the brain showed cortical T2 prolongation with significant enhancement with gadolinium in the cortex and leptomeninges of the left parietal and posterotemporal lobes and right cingulate gyrus region (Fig. 1). The patient was admitted to the intensive care unit, and phenytoin and levetiracetam were administered. Over the next several days, she remained afebrile, and her leukocytosis resolved. She continued to have seizures every day despite receiving phenytoin, levetiracetam, and lamotrigine. She was alert and complained about persistent right arm weakness and word‐finding difficulties. Posterior cervical lymphadenopathy at the base of her left occiput was detected on subsequent exam.

Figure 1

An excisional lymph node biopsy demonstrated extensive necrosis without evidence of granulomata, malignancy, or lymphoproliferative disease. Stains and cultures for bacteria, fungi, and mycobacteria were negative. The patient's electroencephalogram captured epileptiform activity over the left hemisphere 2 hours after a cluster of seizures. MR angiography and cerebral angiography demonstrated no abnormalities.

Despite this additional information, there is no distinguishing clue that points to a single diagnosis. This is a 26‐year‐old healthy, seemingly immunocompetent woman who has had a 2‐week progressive and refractory seizure disorder secondary to a multifocal neuroinvasive process with a CSF pleocytosis. She does not have evidence of a systemic underlying disorder, save for nonspecific localized lymphadenopathy and a transient episode of leukocytosis on admission, and has no distinguishing epidemiological factors or exposures.

Despite my initial concerns for infectious meningoencephalitis, the negative stains, serologies, and cultures of the blood, CSF, and lymph nodes in the setting of a normal immune system and no suspect exposure substantially lower this probability. Arthropod‐borne viruses are still possible, especially West Nile virus, because the serological tests are less sensitive early in the illness, acknowledging that the absence of fever, weakness, and known mosquito bites detracts from this diagnosis. Pathogens that cause regional lymphadenopathy and encephalitis such as Bartonella remain possibilities, as the history of exposure to a kitten can be easily overlooked.

Rheumatologic disorders merit close attention in a young woman, but the negative ANA makes lupus cerebritis unlikely, and the 2 angiograms did not detect evidence of vasculitis. Finally, there is the question of malignancy and other miscellaneous infiltrative disorders (such as sarcoid), which are of importance here because of the multifocal cortical involvement on imaging.

At this point, I would resample the CSF for viral etiologies (eg, West Nile virus) and cytology and would send serum Bartonella serologies. If these studies were negative, a brain biopsy, primarily to exclude malignancy but also to uncover an unsuspected process, would be indicated. I cannot make a definitive diagnosis or find a perfect fit here, but in the absence of strong evidence of an infection, I am concerned about a malignancy, perhaps a low‐grade primary brain tumor.

Brain biopsy of the leptomeninges and cortex of the left parietal lobe showed multiple blood vessels infiltrated by lymphocytes, neutrophils, and eosinophils (Fig. 2). The pattern of inflammation was consistent with primary angiitis of the central nervous system (PACNS). The patient received 1 g of intravenous methylprednisolone on 3 consecutive days, followed by oral prednisone and cyclophosphamide. The seizures ceased, and she made steady progress with rehabilitation therapy. Four months after discharge a cerebral angiogram (done to ensure there was no interval evidence of vasculitis prior to tapering therapy) demonstrated patency of all major intracranial arteries and venous sinuses.

Figure 2

COMMENTARY

When a patient presents with symptoms or signs referable to the central nervous system (CNS), hospitalists must simultaneously consider primary neurologic disorders and systemic diseases that involve the CNS. Initial evaluation includes a thorough history and physical examination, basic lab studies, routine CSF analysis, and neuroimaging (often a CT scan of the head). Complicated neurologic cases may warrant more elaborate testing including EEG, brain MRI, cerebral angiography, and specialized blood and CSF studies. Clinicians may still find themselves faced with a patient who has clear CNS dysfunction but no obvious diagnosis despite an exhaustive and expensive evaluation. Several disorders match this profile including intravascular lymphoma, prion diseases, paraneoplastic syndromes, and cerebritis. Primary angiitis of the central nervous system (PACNS), a rare disorder characterized by inflammation of the medium‐sized and small arteries of the CNS, is among these disorders. Although the aforementioned diseases may sometimes have suggestive or even pathognomonic features (eg, the string of beads angiographic appearance in vasculitides), they are challenging to diagnose when such findings are absent.

Like any vasculitis of the CNS, PACNS may present with a wide spectrum of clinical features.12 Although headache and altered mental status are the most common complaints, paresis, seizures, ataxia, visual changes, and aphasia have all been described. The onset of symptoms ranges from acute to chronic, and neurologic deficits can be focal or diffuse. Systemic manifestations such as fever and weight loss are rare. The average age of onset is 42 years, with no significant sex preponderance. The histopathology of PACNS is granulomatous inflammation of arteries in the parenchyma and leptomeninges of the brain and less commonly in the spinal cord. The narrowing of the affected vessels causes cerebral ischemia and the associated neurologic deficits. The trigger for this focal inflammation is unknown.

After common disorders have been excluded in cases of CNS dysfunction, compatible CSF findings and imaging results may prompt consideration of PACNS. CSF analysis in patients with PACNS typically demonstrates a lymphocytic pleocytosis. MRI abnormalities in PACNS include multiple infarcts in the cortex, deep white matter, or leptomeninges.34 Less specific findings are contrast enhancement in the leptomeninges and white matter disease, both of which may direct the site for meningeal and brain biopsy.

Both brain MRA and cerebral angiography have a limited role in the diagnosis of vasculitis within the CNS. In 18 patients with CNS vasculitis due to autoimmune disease, all had parenchymal abnormalities on MRA but only 65% had evidence of vasculitis on angiography. In 2 retrospective studies of patients with suspected PACNS, abnormal angiograms had a specificity less than 30% for PACNS, whereas brain biopsies had a negative predictive value of 70%.57 Although in practice patients with compatible clinical features are sometimes diagnosed with CNS vasculitis on the basis of angiographic findings, brain biopsy is necessary to differentiate vasculitis from other vasculopathies and to establish a definitive diagnosis.

Before a diagnosis of PACNS is made, care must be taken to exclude infections, neoplasms, and autoimmune processes that cause angiitis of the CNS (Table 1). The presence of any extracranial abnormalities (which were not present in this case) should prompt consideration of an underlying systemic disorder causing a secondary CNS vasculitis and should cast doubt on the diagnosis of PACNS. Meningovascular syphilis and tuberculosis are among the long list of infections that may cause inflammation of the CNS vasculature. Autoimmune disorders that may cause vasculitis inside the brain include polyarteritis nodosa and Wegener's granulomatosis. Reversible cerebral vasoconstrictive disease, which is most commonly seen in women ages 20 to 50, and sympathomimetic toxins such as cocaine and amphetamine may exhibit clinical and angiographic abnormalities indistinguishable from PACNS.89

There are no prospective trials investigating PACNS treatment. Aggressive immunosuppression with cyclophosphamide and glucocorticoids is the mainstay of treatment. The duration of treatment varies with the severity of the disease and response to therapy. One study suggests that treatment should be continued for 6 to 12 months.10 Neurologic deficits may remain irreversible because of scarring of the affected vessels. Serial brain MRI examinations are often used to follow radiographic resolution during and after the therapy, although radiographic changes do not predict clinical response.11 New abnormalities on MRI, however, delay any tapering of treatment. The availability of neuroimaging studies and immunosuppressive therapy has improved the prognosis of PACNS. One study reported a favorable outcome with a 29% relapse rate and a 10% mortality rate in 54 patients over a mean follow‐up period of 35 months.12

PACNS remains a challenging diagnosis because of its rarity, the wide range of neurologic manifestations, and the difficulty in establishing a diagnosis noninvasively. It is an extremely uncommon disease but should be considered in patients with unexplained neurologic deficits referable to the CNS alone after an exhaustive workup. Ultimately, the diagnosis is made by a thorough history and physical examination, exclusion of underlying conditions (particularly systemic vasculitides and infections), and histological confirmation.

A 26‐year‐old woman was brought to the emergency department following several episodes of seizures. The patient's friend witnessed several 15‐minute episodes of sudden jerks and tremors of her right arm during which the patient bit her tongue, had word‐finding difficulty, had horizontal eye deviation, and was incontinent of urine. She became unresponsive during the episodes, with incomplete recovery of consciousness between attacks. She was afebrile. Her neurologic exam 4 hours after several seizures revealed word‐finding difficulty and right arm weakness. A complete blood count, chemistry panel including renal and liver function tests, urine toxicology screen, and computed tomography (CT) of the head were normal. After a loading dose of fosphenytoin, the patient did not experience further seizures and was discharged on a maintenance dose of phenytoin.

Over the next week, the patient continued to note a sensation of heaviness in her right arm and felt fatigued. The patient's mother brought her back to the emergency department after witnessing a similar seizure episode that persisted for an hour. On arrival, the patient was no longer seizing.

Although it can sometimes be difficult to differentiate between seizure, stroke, syncope, and other causes of transient loss of consciousness, this constellation of symptoms strongly points to a seizure. I would classify the patient's focal arm movements associated with impaired consciousness as partial complex seizures. One of the first considerations is determining whether the seizure is caused by a systemic process or by an intrinsic central nervous system disorder. Common systemic illnesses include infections, metabolic disturbances, toxins, and malignancies, none of which are evident on the preliminary evaluation. The absence of fever is important as is the time frame (now extending over 1 week) in excluding acute bacterial meningitis. A negative urine toxicology is very helpful but does not exclude the possibility that the seizure is from unmeasured drug intoxication, for example, tricyclic antidepressants, or from drug withdrawal, for example, benzodiazepines, barbiturates, ethanol, and antiepileptic drugs. The persistent right arm heaviness and right arm jerking during the seizures suggest a left cortical focus that the CT scan did not detect. Without a clear diagnosis and with recurrent seizures despite antiepileptic drugs, hospitalization is warranted.

The patient experienced migraine headaches each month during menses. There was no family history of seizures. Her only medication was phenytoin. The mother was unaware of any use of tobacco, alcohol, or recreational drugs. The patient was raised in New Jersey and moved to the San Francisco Bay area 9 months ago. She had no pets and had traveled to Florida and Montreal in the past 6 months. She was a graduate student in performing arts. During the preceding 2 weeks she had been under significant stress and had not slept much in preparation for an upcoming production. The patient's mother was not aware of any head trauma, recent illness, fevers, chills, weight loss, photosensitivity, arthralgias, nausea, vomiting, or diarrhea.

Recent sleep deprivation could provoke seizures in a patient with a latent anatomic focus or metabolic predisposition. Nonadherence to antiepileptic drug therapy is the most common reason for patients to present to the ED with seizures; therefore, I would check a phenytoin level to assess whether she is at a therapeutic level and would consider administering another loading dose. In the absence of immunocompromise or unusual activities or exposures, North American travel does not bring to mind additional etiologies at this time.

On exam, temperature was 37.3C, blood pressure was 148/84 mm Hg, heart rate was 120 per minute, and respiratory rate was 16 per minute. The patient was stuporous and withdrew from painful stimuli. She was unable to speak. Pupils were 4 mm in diameter and reacted to light. No gaze preference or nystagmus was present. There was no meningismus. Deep tendon reflexes were 1+ and symmetrical in both upper and lower extremities. Plantar reflexes were extensor bilaterally. The tone in the right upper extremity was mildly increased compared to the left. The patient demonstrated semipurposeful movement of the limbs, such as reaching for the bed rails with her arms. Examination of the heart, lungs, abdomen, skin, and oropharynx was normal.

The white blood cell count was 22,300/mm³ with 50% neutrophils, 40% lymphocytes, 7% monocytes, and 3% eosinophils. Results of the chemistry panel including electrolytes, glucose, creatinine, and liver enzymes, urinalysis, and thyroid‐stimulating hormone were normal. Serum phenytoin level was 8.1 g/mL. Urine toxicology screen, obtained after the patient had received lorazepam, was positive only for benzodiazepines. A chest radiograph was normal.

The cerebrospinal fluid (CSF) was colorless, containing 35 white blood cells/mm³ (48% lymphocytes, 30% neutrophils, 22% monocytes), 3 red blood cells/mm³, 62 mg/dL protein, and 50 mg/dL glucose. There was no xanthochromia. The CSF was negative for cryptococcal antigen, antibodies to West Nile virus, PCR for herpes simplex viruses‐1 and ‐2, and PCR for Borrelia burgdorferi. CSF bacterial culture, cryptococcal antigen, and AFB stain were negative. The serum antinuclear antibody, rheumatoid factor, and rapid plasma reagin were negative. Serum antibodies to human immunodeficiency virus, hepatitis B and C viruses, Borrelia burgdorferi, and herpes simplex viruses were negative. The erythrocyte sedimentation rate was 25 mm/hr. There was no growth in her blood cultures.

These CSF findings have to be interpreted in light of her clinical picture, as they are congruent with both an aseptic meningitis and encephalitis. In practice, these can be hard to distinguish, but the early and dominant cortical findings (focal neurologic deficits, prominent altered mental status, bilateral extensor plantar reflexes) and absence of meningeal signs favor encephalitis. This CSF profile can be seen in a variety of disease processes causing a meningoencephalitis, including partially treated bacterial meningitis; meningitis due to viruses, fungi, mycobacteria, or atypical bacteria (eg, Listeria); neurosarcoidosis; carcinomatous meningitis; and infection or inflammation from a parameningeal focus in the sinuses, epidural space, or brain parenchyma. Seizure itself can lead to a postictal pleocytosis in the CSF, although this degree of inflammation would be unusual. Many tests can be sent, and the clinicians appropriately focused on some of the most treatable and serious etiologies first. The negative HIV test limits the list of opportunistic pathogens. The negative ANA substantially lowers the likelihood of systemic lupus, an important consideration in a young woman with an inflammatory disorder involving the central nervous system.

Magnetic resonance imaging (MRI) of the brain showed cortical T2 prolongation with significant enhancement with gadolinium in the cortex and leptomeninges of the left parietal and posterotemporal lobes and right cingulate gyrus region (Fig. 1). The patient was admitted to the intensive care unit, and phenytoin and levetiracetam were administered. Over the next several days, she remained afebrile, and her leukocytosis resolved. She continued to have seizures every day despite receiving phenytoin, levetiracetam, and lamotrigine. She was alert and complained about persistent right arm weakness and word‐finding difficulties. Posterior cervical lymphadenopathy at the base of her left occiput was detected on subsequent exam.

Figure 1

An excisional lymph node biopsy demonstrated extensive necrosis without evidence of granulomata, malignancy, or lymphoproliferative disease. Stains and cultures for bacteria, fungi, and mycobacteria were negative. The patient's electroencephalogram captured epileptiform activity over the left hemisphere 2 hours after a cluster of seizures. MR angiography and cerebral angiography demonstrated no abnormalities.

Despite this additional information, there is no distinguishing clue that points to a single diagnosis. This is a 26‐year‐old healthy, seemingly immunocompetent woman who has had a 2‐week progressive and refractory seizure disorder secondary to a multifocal neuroinvasive process with a CSF pleocytosis. She does not have evidence of a systemic underlying disorder, save for nonspecific localized lymphadenopathy and a transient episode of leukocytosis on admission, and has no distinguishing epidemiological factors or exposures.

Despite my initial concerns for infectious meningoencephalitis, the negative stains, serologies, and cultures of the blood, CSF, and lymph nodes in the setting of a normal immune system and no suspect exposure substantially lower this probability. Arthropod‐borne viruses are still possible, especially West Nile virus, because the serological tests are less sensitive early in the illness, acknowledging that the absence of fever, weakness, and known mosquito bites detracts from this diagnosis. Pathogens that cause regional lymphadenopathy and encephalitis such as Bartonella remain possibilities, as the history of exposure to a kitten can be easily overlooked.

Rheumatologic disorders merit close attention in a young woman, but the negative ANA makes lupus cerebritis unlikely, and the 2 angiograms did not detect evidence of vasculitis. Finally, there is the question of malignancy and other miscellaneous infiltrative disorders (such as sarcoid), which are of importance here because of the multifocal cortical involvement on imaging.

At this point, I would resample the CSF for viral etiologies (eg, West Nile virus) and cytology and would send serum Bartonella serologies. If these studies were negative, a brain biopsy, primarily to exclude malignancy but also to uncover an unsuspected process, would be indicated. I cannot make a definitive diagnosis or find a perfect fit here, but in the absence of strong evidence of an infection, I am concerned about a malignancy, perhaps a low‐grade primary brain tumor.

Brain biopsy of the leptomeninges and cortex of the left parietal lobe showed multiple blood vessels infiltrated by lymphocytes, neutrophils, and eosinophils (Fig. 2). The pattern of inflammation was consistent with primary angiitis of the central nervous system (PACNS). The patient received 1 g of intravenous methylprednisolone on 3 consecutive days, followed by oral prednisone and cyclophosphamide. The seizures ceased, and she made steady progress with rehabilitation therapy. Four months after discharge a cerebral angiogram (done to ensure there was no interval evidence of vasculitis prior to tapering therapy) demonstrated patency of all major intracranial arteries and venous sinuses.

Figure 2

COMMENTARY

When a patient presents with symptoms or signs referable to the central nervous system (CNS), hospitalists must simultaneously consider primary neurologic disorders and systemic diseases that involve the CNS. Initial evaluation includes a thorough history and physical examination, basic lab studies, routine CSF analysis, and neuroimaging (often a CT scan of the head). Complicated neurologic cases may warrant more elaborate testing including EEG, brain MRI, cerebral angiography, and specialized blood and CSF studies. Clinicians may still find themselves faced with a patient who has clear CNS dysfunction but no obvious diagnosis despite an exhaustive and expensive evaluation. Several disorders match this profile including intravascular lymphoma, prion diseases, paraneoplastic syndromes, and cerebritis. Primary angiitis of the central nervous system (PACNS), a rare disorder characterized by inflammation of the medium‐sized and small arteries of the CNS, is among these disorders. Although the aforementioned diseases may sometimes have suggestive or even pathognomonic features (eg, the string of beads angiographic appearance in vasculitides), they are challenging to diagnose when such findings are absent.

Like any vasculitis of the CNS, PACNS may present with a wide spectrum of clinical features.12 Although headache and altered mental status are the most common complaints, paresis, seizures, ataxia, visual changes, and aphasia have all been described. The onset of symptoms ranges from acute to chronic, and neurologic deficits can be focal or diffuse. Systemic manifestations such as fever and weight loss are rare. The average age of onset is 42 years, with no significant sex preponderance. The histopathology of PACNS is granulomatous inflammation of arteries in the parenchyma and leptomeninges of the brain and less commonly in the spinal cord. The narrowing of the affected vessels causes cerebral ischemia and the associated neurologic deficits. The trigger for this focal inflammation is unknown.

After common disorders have been excluded in cases of CNS dysfunction, compatible CSF findings and imaging results may prompt consideration of PACNS. CSF analysis in patients with PACNS typically demonstrates a lymphocytic pleocytosis. MRI abnormalities in PACNS include multiple infarcts in the cortex, deep white matter, or leptomeninges.34 Less specific findings are contrast enhancement in the leptomeninges and white matter disease, both of which may direct the site for meningeal and brain biopsy.

Both brain MRA and cerebral angiography have a limited role in the diagnosis of vasculitis within the CNS. In 18 patients with CNS vasculitis due to autoimmune disease, all had parenchymal abnormalities on MRA but only 65% had evidence of vasculitis on angiography. In 2 retrospective studies of patients with suspected PACNS, abnormal angiograms had a specificity less than 30% for PACNS, whereas brain biopsies had a negative predictive value of 70%.57 Although in practice patients with compatible clinical features are sometimes diagnosed with CNS vasculitis on the basis of angiographic findings, brain biopsy is necessary to differentiate vasculitis from other vasculopathies and to establish a definitive diagnosis.

Before a diagnosis of PACNS is made, care must be taken to exclude infections, neoplasms, and autoimmune processes that cause angiitis of the CNS (Table 1). The presence of any extracranial abnormalities (which were not present in this case) should prompt consideration of an underlying systemic disorder causing a secondary CNS vasculitis and should cast doubt on the diagnosis of PACNS. Meningovascular syphilis and tuberculosis are among the long list of infections that may cause inflammation of the CNS vasculature. Autoimmune disorders that may cause vasculitis inside the brain include polyarteritis nodosa and Wegener's granulomatosis. Reversible cerebral vasoconstrictive disease, which is most commonly seen in women ages 20 to 50, and sympathomimetic toxins such as cocaine and amphetamine may exhibit clinical and angiographic abnormalities indistinguishable from PACNS.89

There are no prospective trials investigating PACNS treatment. Aggressive immunosuppression with cyclophosphamide and glucocorticoids is the mainstay of treatment. The duration of treatment varies with the severity of the disease and response to therapy. One study suggests that treatment should be continued for 6 to 12 months.10 Neurologic deficits may remain irreversible because of scarring of the affected vessels. Serial brain MRI examinations are often used to follow radiographic resolution during and after the therapy, although radiographic changes do not predict clinical response.11 New abnormalities on MRI, however, delay any tapering of treatment. The availability of neuroimaging studies and immunosuppressive therapy has improved the prognosis of PACNS. One study reported a favorable outcome with a 29% relapse rate and a 10% mortality rate in 54 patients over a mean follow‐up period of 35 months.12

PACNS remains a challenging diagnosis because of its rarity, the wide range of neurologic manifestations, and the difficulty in establishing a diagnosis noninvasively. It is an extremely uncommon disease but should be considered in patients with unexplained neurologic deficits referable to the CNS alone after an exhaustive workup. Ultimately, the diagnosis is made by a thorough history and physical examination, exclusion of underlying conditions (particularly systemic vasculitides and infections), and histological confirmation.

A 65‐year‐old man was referred for evaluation of worsening ascites and end‐stage liver disease. The patient had been well until 1 year ago, when he developed lower extremity edema and abdominal distention. After evaluation by his primary care physician, he was given a diagnosis of cryptogenic cirrhosis. He underwent several paracenteses and was placed on furosemide and spironolactone. The patient had been stable on his diuretic regimen until 2 weeks previously, when he suddenly developed worsening edema and ascites, along with dizziness, nausea, and hypotension. His physician stopped the diuretics and referred him to the hospital.

Before diagnosing a patient with cryptogenic cirrhosis, it is necessary to exclude common etiologies of cirrhosis such as alcohol, viral hepatitis, and non‐alcoholic fatty liver disease and numerous uncommon causes, including Wilson's disease, hemochromatosis, Budd‐Chiari, and biliary cirrhosis. It is also important to remember that patients with liver disease are not immune to extrahepatic causes of ascites, such as peritoneal carcinomatosis and tuberculous ascites. Simultaneously, reasons for chronic liver disease decompensating acutely must be considered: medication nonadherence, excess salt intake, hepatotoxicity from acetaminophen or alcohol, and other acute insults, such as hepatocellular carcinoma, an intervening infection (especially spontaneous bacterial peritonitis), ascending cholangitis, or a flare of chronic viral hepatitis.

Past medical and surgical history included diabetes mellitus (diagnosed 10 years previously), obstructive sleep apnea, hypertension, hypothyroidism, and mild chronic kidney disease. Medications included levothyroxine, lactulose, sulfamethoxazole, pioglitazone (started 4 months prior), and ibuprofen. Furosemide and spironolactone had been discontinued 2 weeks previously. He currently resided in the Central Valley of California. He had lived in Thailand from age 7 to 17 and traveled to India more than 1 year ago. He did not smoke and had never used intravenous drugs or received a blood transfusion. He rarely drank alcohol. He worked as a chemist. There was no family history of liver disease.

There is no obvious explanation for the underlying liver disease or the acute decompensation. Sulfamethoxazole is a rare cause of allergic or granulomatous hepatitis. Pioglitazone is a thiazolinedione which in earlier formulations was linked to hepatitis but can be excluded as a cause of this patient's cirrhosis because it was started after liver disease was detected. As a chemist, he might have been exposed to carbon tetrachloride, a known hepatotoxin. Obstructive sleep apnea causes pulmonary hypertension, but severe ascites and acute hepatic decompensation would be unusual. Ibuprofen might precipitate worsening renal function and fluid accumulation. Time in Thailand and India raises the possibility of tuberculous ascites.

The patient had no headache, vision changes, abdominal pain, emesis, melena, hematochezia, chest pain, palpitations, dysuria, polyuria, pruritus, dark urine, or rashes. He reported difficulty with concentration when lactulose was decreased. He noted worsening exercise tolerance with dyspnea after 10 steps and reported a weight gain of 12 pounds in the past 2 weeks.

On examination, temperature was 36.8C; blood pressure, 129/87 mm Hg; heart rate, 85 beats per minute; respirations, 20 per minute; and oxygen saturation, 94% on room air. He was uncomfortable but alert. There was no scleral icterus or conjunctival pallor. Jugular venous pressure was elevated. The lungs were clear, and the heart was regular, with no murmur, rub, or gallops. The abdomen was massively distended with a fluid wave; the liver and spleen could not be palpated. There was pitting edema of the sacrum and lower extremities. There was no asterixis, palmar erythema, spider angiomata, or skin discoloration.

The additional history and physical exam suggest that the primary problem may lie outside the liver, especially as signs of advanced liver disease (other than ascites) are absent. Dyspnea on exertion is consistent with the physical stress of a large volume of ascites or could be secondary to several pulmonary complications associated with liver disease, including portopulmonary hypertension, hepatopulmonary syndrome, or hepatic hydrothorax. Alternatively, the dyspnea raises the possibility that the ascites is not related to a primary liver disorder but rather to anemia or to a cardiac disorder, such as chronic left ventricular failure, isolated right‐sided heart failure, or constrictive pericarditis. These diagnoses are suggested by the elevated jugular venous pressure, which is atypical in cirrhosis.

Although portal hypertension accounts for most cases of ascites, peritoneal fluid should be examined to exclude peritoneal carcinomatosis and tuberculous ascites. I am interested in the results of an echocardiogram.

Initial laboratory studies demonstrated a sodium concentration of 136 mEq/dL; potassium, 4.7 mEq/dL; chloride, 99 mEq/dL; bicarbonate, 24 mEq/dL; blood urea nitrogen, 54 mg/dL; creatinine, 3.3 mg/dL (increased from baseline of 1.6 mg/dL 4 months previously); white cell count, 7000/mm³; hemoglobin, 10.5 g/dL; MCV, 89 fL; platelet count, 205,000/mm³; bilirubin, 0.6 mg/dL; aspartate aminotransferase, 15 U/L; alanine aminotransferase, 8 U/L; alkaline phosphatase, 102 U/L; albumin, 4.2 g/dL; total protein, 8.2 g/dL; international normalized ratio, 1.2; and partial thromboplastin time, 31.8 seconds. A urine dipstick demonstrated 1+ protein. The chest radiograph was normal. Electrocardiogram had borderline low voltage with nonspecific T‐wave abnormalities. Additional studies showed a serum iron concentration of 49 mg/dL, transferrin saturation of 16%, total iron binding capacity of 310 mg/dL, and ferritin of 247 mg/mL. Hemoglobin A1c was 7.0%. Acute and chronic antibodies to hepatitis A, B, and C viruses were negative. The following study results were normal or negative: antinuclear antibody, alpha‐1‐antitrypsin, ceruloplasmin, alpha‐fetoprotein, carcinoembryonic antigen, and 24‐hour urinary copper. The thyroid function studies were normal. A purified protein derivative (PPD) skin test was nonreactive.

There continues to be a paucity of evidence of a primary liver disorder. The hepatic enzymes and tests of liver synthetic function are normal, and there is no pancytopenia, as might result from hypersplenism. I remain most suspicious of either a primary cardiac or pericardial disorder with secondary hepatic congestion or a disease that simultaneously affects the heart and liver.

The reasons for the low voltage on the electrocardiogram include processes that infiltrate the myocardium (amyloidosis, sarcoidosis, hemochromatosis, and myxedema fluid) and processes that increase the distance between the myocardium and surface electrodes, such as adipose tissue, air (from emphysema or pneumothorax), or pericardial effusion. Pericardial effusion may present subacutely with predominant features of right ventricular failure. Low voltage, liver disease, and possible heart failure raise the possibility of amyloidosis or hemochromatosis. The low transferrin saturation renders hemochromatosis unlikely. Although normal alkaline phosphatase and serum albumin are not characteristic when AL amyloid affects the liver and kidneys, serum and urine protein electrophoresis and immunofixation should be considered.

With paracentesis 3.5 L of ascitic fluid was removed. The red cell count was 4000/mm³, and white blood cell count was 505/mm³, of which 25% were polymorphonuclear cells, 22% were lymphocytes, and 53% were monocytes. Additional peritoneal fluid chemistries included albumin of 3.0 g/dL and total protein of 5.3 g/dL. Abdominal ultrasound with Doppler demonstrated a liver of normal size and echogenicity with patent hepatic arteries, hepatic veins, and portal vein. There was mild splenomegaly with normal kidneys. Evaluation for a possible liver transplant was initiated. Blood, urine, and peritoneal fluid cultures demonstrated no growth. Echocardiography demonstrated borderline concentric left ventricular hypertrophy, normal right and left ventricular function, dilated superior and inferior vena cavae, and no pericardial effusion or thickening.

The serum‐ascites albumin gradient (SAAG) of 1.2 is consistent with portal hypertension as the cause of the ascites. The Doppler findings exclude postsinusoidal causes of portal hypertension from hepatic vein obstruction or thrombosis. The combination of the elevated SAAG, elevated jugular venous pressure, borderline low voltage on ECG, and elevated peritoneal total protein make cardiac and pericardial disease the leading considerations. Given the normal ventricular function, I am concerned about elevated intracardiac pressures resulting from pericardial disease or restrictive cardiomyopathy. At this point, right heart catheterization would be useful for assessing intracardiac pressures.

On the fourth hospital day, paracentesis was repeated, and 15 L of fluid was removed. A transjugular liver biopsy demonstrated diffuse patchy fibrosis consistent with early cirrhosis and minor intralobular changes with minimal ballooning. There was no steatosis, active inflammation, granulomata, iron deposition, or evidence of viral hepatitis. Right heart catheterization revealed a right atrial pressure of 18 cm H₂0, right ventricular pressure of 34/20 cm H₂0, pulmonary artery pressure of 34/18 cm H₂0 (mean 25), pulmonary capillary wedge pressure of 20 cm H₂0, cardiac output of 5.8 L/min, and cardiac index of 2.5 L/min/m².

The mild hepatic histologic abnormalities do not support an intrinsic liver disease as the cause of his massive ascites and end‐stage liver disease physiology. Cardiac catheterization demonstrates equalization of diastolic pressures, which suggests constrictive pericarditis or restrictive cardiomyopathy. Despite the normal chest radiograph and nonreactive PPD, tuberculosis would be my leading explanation for constrictive pericarditis given the time spent in areas endemic with TB. Although lateral chest radiography may demonstrate pericardial calcifications, magnetic resonance imaging (MRI) is the best imaging modality to detect constrictive pericarditis. Alternately, cardiac amyloidosis could cause restrictive cardiomyopathy and has not been definitively excluded. A cardiac MRI to assess the pericardium would be my next test, and I would request Congo red stains of the liver biopsy. If these tests are unrevealing, endomyocardial biopsy may be necessary.

The cardiac MRI revealed a severely thickened 7‐mm pericardium (normal < 3 mm) most prominent over the right atrium and ventricle. The right ventricle was described as bullet‐shaped, suggesting constrictive pericardial disease (Fig. 1). Left heart catheterization to evaluate coronary anatomy and left ventricular pressures revealed no significant coronary arterial disease and demonstrated an elevated left ventricular end‐diastolic pressure consistent with constrictive pericarditis. Endomyocardial biopsy showed no evidence of infiltrative disease, granulomata, or other significant abnormality. The following day the patient underwent pericardiectomy. Postoperatively, his ascites was easily managed with low doses of diuretics. The pericardial tissue revealed chronic inflammatory cells and dense collagenous fibrosis characteristic of constrictive pericarditis without evidence of malignancy or granulomatous disease. Pericardial cultures were negative for bacteria, viruses, fungi, and mycobacteria.

Figure 1

DISCUSSION

Constrictive pericarditis is characterized by chronic fibrous thickening of the once‐elastic pericardial sac and can occur following any disease process that affects the pericardium (Table 1).1, 2 The challenge in the diagnosis of constrictive pericarditis lies in the recognition of this slowly progressive and uncommon disease. In many cases, nonspecific symptoms of reduced cardiac output and insidious right‐sided heart failure are present for 12 months or longer before a diagnosis is established.1, 3 A typical presentation of constrictive pericarditis is peripheral edema, ascites, and hepatomegaly, a combination that may understandably lead to a misdiagnosis of chronic liver disease and even subject a patient to the unnecessary risk of a liver biopsy, as in this case.

Cryptogenic cirrhosis, the initial diagnosis of this patient, is a term used only after excluding the common and uncommon causes of cirrhosis (Table 2).46 With expanded knowledge of the causes of cirrhosis, especially nonalcoholic fatty liver disease, the number of cases of cirrhosis considered to be cryptogenic has decreased from nearly one‐third of all cases in 1960 to approximately 5% in a modern series.7, 8 Chronic or repetitive heart failure can lead to progressive hepatic fibrosis and cirrhosis. Distinguishing features compared to other causes of cirrhosis include an ascitic protein concentration greater than 2.5 g/dL, relatively preserved synthetic function, and infrequent stigmata of end‐stage liver disease such as spider angiomata or pronounced jaundice.9, 10

A key exam feature that distinguishes cardiac cirrhosis from other causes of liver failure is an elevated jugular venous pressure. Hepatic causes of cirrhosis induce increased nitric oxide production, which leads to splanchnic and peripheral arterial vasodilatation with a reduced effective circulating volume and normal or low jugular venous pressure.11, 12 Therefore, a patient with cirrhosis and ascites having an elevated jugular venous pressure should prompt echocardiographic evaluation.13 When echocardiography excludes ventricular dysfunction, valvular abnormalities, and pulmonary hypertension, constrictive pericarditis and restrictive cardiomyopathy remain important diagnostic considerations.

In both constrictive pericarditis and restrictive cardiomyopathy, ventricular filling is limited. Pressures in the chambers rise abruptly and rapidly during ventricular filling until equilibrium is reached in early diastole. This can be conceptualized as the cardiac chambers being constrained by the limitations of a rigid external box. In constrictive pericarditis, the rigid external box is the fibrosed and thickened pericardial sac, which loses its elasticity and impairs filling of the ventricles. In restrictive cardiomyopathy, the stiff myocardium limits ventricular filling.

There is considerable overlap in the clinical, echocardiographic, and hemodynamic findings of constrictive pericarditis and restrictive cardiomyopathy.14 Both may present insidiously with progressive heart failure. Echocardiography demonstrates impaired diastolic function. Cardiac hemodynamics demonstrate abrupt and rapid early diastolic filling, elevated and equal ventricular end‐diastolic pressures, and reduced stroke volume and cardiac output. A diagnosis of constrictive pericarditis is favored when a marked inspiratory increase in right ventricular pressures and decrease in left ventricular pressures are seen on heart catheterization or a similar inspiratory increase in transvalvular flow velocities across the tricuspid valve compared with the mitral valve is shown by echocardiography. This finding results from normal inspiratory increases in intrathoracic pressures, which are unable to be transmitted through the rigid pericardium but continue to augment venous return to the right side of the heart. As many as one‐third of patients with pericardial constriction lack these characteristic findings on echocardiogram.14

The results of pericardial imaging may suggest a diagnosis of constrictive pericarditis. Lateral chest radiography demonstrates pericardial calcifications in less than 30% of cases.15 Cardiac computed tomography (CT) and MRI are the best imaging modalities for detecting an increase in pericardial thickness (3 mm or greater).16 However, in as many as 20% of patients with surgically confirmed constrictive pericarditis, CT and MRI will demonstrate a pericardium of normal thickness.17

When faced with the diagnostic conundrum of constrictive pericarditis versus restrictive cardiomyopathy, strong clinical suspicion, thorough echocardiography, careful hemodynamic assessment with right and left heart catheterization,14, 18 pericardial imaging, and sometimes endomyocardial biopsy to exclude restrictive cardiomyopathy are often needed before proceeding to pericardiectomy, which carries a significant surgical risk but can also be curative.

This case highlights many of the features of constrictive pericarditis, the challenges and delay in its diagnosis, and its occasional misdiagnosis as chronic liver disease. Clinicians may recognize the typical combination of cirrhosis (or suspected cirrhosis), high SAAG ascites, and edema as characteristic of advanced intrinsic liver disease. However, they must not be seduced into immediate pattern recognition when contrary evidencesuch as elevated neck veins, elevated ascitic total protein, or relatively preserved hepatic synthetic functionaccompanies that picture. Under such circumstances, they must remember to think outside the box and bear in mind that the heart may be trapped inside a box.

A 65‐year‐old man was referred for evaluation of worsening ascites and end‐stage liver disease. The patient had been well until 1 year ago, when he developed lower extremity edema and abdominal distention. After evaluation by his primary care physician, he was given a diagnosis of cryptogenic cirrhosis. He underwent several paracenteses and was placed on furosemide and spironolactone. The patient had been stable on his diuretic regimen until 2 weeks previously, when he suddenly developed worsening edema and ascites, along with dizziness, nausea, and hypotension. His physician stopped the diuretics and referred him to the hospital.

Before diagnosing a patient with cryptogenic cirrhosis, it is necessary to exclude common etiologies of cirrhosis such as alcohol, viral hepatitis, and non‐alcoholic fatty liver disease and numerous uncommon causes, including Wilson's disease, hemochromatosis, Budd‐Chiari, and biliary cirrhosis. It is also important to remember that patients with liver disease are not immune to extrahepatic causes of ascites, such as peritoneal carcinomatosis and tuberculous ascites. Simultaneously, reasons for chronic liver disease decompensating acutely must be considered: medication nonadherence, excess salt intake, hepatotoxicity from acetaminophen or alcohol, and other acute insults, such as hepatocellular carcinoma, an intervening infection (especially spontaneous bacterial peritonitis), ascending cholangitis, or a flare of chronic viral hepatitis.

Past medical and surgical history included diabetes mellitus (diagnosed 10 years previously), obstructive sleep apnea, hypertension, hypothyroidism, and mild chronic kidney disease. Medications included levothyroxine, lactulose, sulfamethoxazole, pioglitazone (started 4 months prior), and ibuprofen. Furosemide and spironolactone had been discontinued 2 weeks previously. He currently resided in the Central Valley of California. He had lived in Thailand from age 7 to 17 and traveled to India more than 1 year ago. He did not smoke and had never used intravenous drugs or received a blood transfusion. He rarely drank alcohol. He worked as a chemist. There was no family history of liver disease.

There is no obvious explanation for the underlying liver disease or the acute decompensation. Sulfamethoxazole is a rare cause of allergic or granulomatous hepatitis. Pioglitazone is a thiazolinedione which in earlier formulations was linked to hepatitis but can be excluded as a cause of this patient's cirrhosis because it was started after liver disease was detected. As a chemist, he might have been exposed to carbon tetrachloride, a known hepatotoxin. Obstructive sleep apnea causes pulmonary hypertension, but severe ascites and acute hepatic decompensation would be unusual. Ibuprofen might precipitate worsening renal function and fluid accumulation. Time in Thailand and India raises the possibility of tuberculous ascites.

The patient had no headache, vision changes, abdominal pain, emesis, melena, hematochezia, chest pain, palpitations, dysuria, polyuria, pruritus, dark urine, or rashes. He reported difficulty with concentration when lactulose was decreased. He noted worsening exercise tolerance with dyspnea after 10 steps and reported a weight gain of 12 pounds in the past 2 weeks.

On examination, temperature was 36.8C; blood pressure, 129/87 mm Hg; heart rate, 85 beats per minute; respirations, 20 per minute; and oxygen saturation, 94% on room air. He was uncomfortable but alert. There was no scleral icterus or conjunctival pallor. Jugular venous pressure was elevated. The lungs were clear, and the heart was regular, with no murmur, rub, or gallops. The abdomen was massively distended with a fluid wave; the liver and spleen could not be palpated. There was pitting edema of the sacrum and lower extremities. There was no asterixis, palmar erythema, spider angiomata, or skin discoloration.

The additional history and physical exam suggest that the primary problem may lie outside the liver, especially as signs of advanced liver disease (other than ascites) are absent. Dyspnea on exertion is consistent with the physical stress of a large volume of ascites or could be secondary to several pulmonary complications associated with liver disease, including portopulmonary hypertension, hepatopulmonary syndrome, or hepatic hydrothorax. Alternatively, the dyspnea raises the possibility that the ascites is not related to a primary liver disorder but rather to anemia or to a cardiac disorder, such as chronic left ventricular failure, isolated right‐sided heart failure, or constrictive pericarditis. These diagnoses are suggested by the elevated jugular venous pressure, which is atypical in cirrhosis.

Although portal hypertension accounts for most cases of ascites, peritoneal fluid should be examined to exclude peritoneal carcinomatosis and tuberculous ascites. I am interested in the results of an echocardiogram.

Initial laboratory studies demonstrated a sodium concentration of 136 mEq/dL; potassium, 4.7 mEq/dL; chloride, 99 mEq/dL; bicarbonate, 24 mEq/dL; blood urea nitrogen, 54 mg/dL; creatinine, 3.3 mg/dL (increased from baseline of 1.6 mg/dL 4 months previously); white cell count, 7000/mm³; hemoglobin, 10.5 g/dL; MCV, 89 fL; platelet count, 205,000/mm³; bilirubin, 0.6 mg/dL; aspartate aminotransferase, 15 U/L; alanine aminotransferase, 8 U/L; alkaline phosphatase, 102 U/L; albumin, 4.2 g/dL; total protein, 8.2 g/dL; international normalized ratio, 1.2; and partial thromboplastin time, 31.8 seconds. A urine dipstick demonstrated 1+ protein. The chest radiograph was normal. Electrocardiogram had borderline low voltage with nonspecific T‐wave abnormalities. Additional studies showed a serum iron concentration of 49 mg/dL, transferrin saturation of 16%, total iron binding capacity of 310 mg/dL, and ferritin of 247 mg/mL. Hemoglobin A1c was 7.0%. Acute and chronic antibodies to hepatitis A, B, and C viruses were negative. The following study results were normal or negative: antinuclear antibody, alpha‐1‐antitrypsin, ceruloplasmin, alpha‐fetoprotein, carcinoembryonic antigen, and 24‐hour urinary copper. The thyroid function studies were normal. A purified protein derivative (PPD) skin test was nonreactive.

There continues to be a paucity of evidence of a primary liver disorder. The hepatic enzymes and tests of liver synthetic function are normal, and there is no pancytopenia, as might result from hypersplenism. I remain most suspicious of either a primary cardiac or pericardial disorder with secondary hepatic congestion or a disease that simultaneously affects the heart and liver.

The reasons for the low voltage on the electrocardiogram include processes that infiltrate the myocardium (amyloidosis, sarcoidosis, hemochromatosis, and myxedema fluid) and processes that increase the distance between the myocardium and surface electrodes, such as adipose tissue, air (from emphysema or pneumothorax), or pericardial effusion. Pericardial effusion may present subacutely with predominant features of right ventricular failure. Low voltage, liver disease, and possible heart failure raise the possibility of amyloidosis or hemochromatosis. The low transferrin saturation renders hemochromatosis unlikely. Although normal alkaline phosphatase and serum albumin are not characteristic when AL amyloid affects the liver and kidneys, serum and urine protein electrophoresis and immunofixation should be considered.

With paracentesis 3.5 L of ascitic fluid was removed. The red cell count was 4000/mm³, and white blood cell count was 505/mm³, of which 25% were polymorphonuclear cells, 22% were lymphocytes, and 53% were monocytes. Additional peritoneal fluid chemistries included albumin of 3.0 g/dL and total protein of 5.3 g/dL. Abdominal ultrasound with Doppler demonstrated a liver of normal size and echogenicity with patent hepatic arteries, hepatic veins, and portal vein. There was mild splenomegaly with normal kidneys. Evaluation for a possible liver transplant was initiated. Blood, urine, and peritoneal fluid cultures demonstrated no growth. Echocardiography demonstrated borderline concentric left ventricular hypertrophy, normal right and left ventricular function, dilated superior and inferior vena cavae, and no pericardial effusion or thickening.

The serum‐ascites albumin gradient (SAAG) of 1.2 is consistent with portal hypertension as the cause of the ascites. The Doppler findings exclude postsinusoidal causes of portal hypertension from hepatic vein obstruction or thrombosis. The combination of the elevated SAAG, elevated jugular venous pressure, borderline low voltage on ECG, and elevated peritoneal total protein make cardiac and pericardial disease the leading considerations. Given the normal ventricular function, I am concerned about elevated intracardiac pressures resulting from pericardial disease or restrictive cardiomyopathy. At this point, right heart catheterization would be useful for assessing intracardiac pressures.

On the fourth hospital day, paracentesis was repeated, and 15 L of fluid was removed. A transjugular liver biopsy demonstrated diffuse patchy fibrosis consistent with early cirrhosis and minor intralobular changes with minimal ballooning. There was no steatosis, active inflammation, granulomata, iron deposition, or evidence of viral hepatitis. Right heart catheterization revealed a right atrial pressure of 18 cm H₂0, right ventricular pressure of 34/20 cm H₂0, pulmonary artery pressure of 34/18 cm H₂0 (mean 25), pulmonary capillary wedge pressure of 20 cm H₂0, cardiac output of 5.8 L/min, and cardiac index of 2.5 L/min/m².

The mild hepatic histologic abnormalities do not support an intrinsic liver disease as the cause of his massive ascites and end‐stage liver disease physiology. Cardiac catheterization demonstrates equalization of diastolic pressures, which suggests constrictive pericarditis or restrictive cardiomyopathy. Despite the normal chest radiograph and nonreactive PPD, tuberculosis would be my leading explanation for constrictive pericarditis given the time spent in areas endemic with TB. Although lateral chest radiography may demonstrate pericardial calcifications, magnetic resonance imaging (MRI) is the best imaging modality to detect constrictive pericarditis. Alternately, cardiac amyloidosis could cause restrictive cardiomyopathy and has not been definitively excluded. A cardiac MRI to assess the pericardium would be my next test, and I would request Congo red stains of the liver biopsy. If these tests are unrevealing, endomyocardial biopsy may be necessary.

The cardiac MRI revealed a severely thickened 7‐mm pericardium (normal < 3 mm) most prominent over the right atrium and ventricle. The right ventricle was described as bullet‐shaped, suggesting constrictive pericardial disease (Fig. 1). Left heart catheterization to evaluate coronary anatomy and left ventricular pressures revealed no significant coronary arterial disease and demonstrated an elevated left ventricular end‐diastolic pressure consistent with constrictive pericarditis. Endomyocardial biopsy showed no evidence of infiltrative disease, granulomata, or other significant abnormality. The following day the patient underwent pericardiectomy. Postoperatively, his ascites was easily managed with low doses of diuretics. The pericardial tissue revealed chronic inflammatory cells and dense collagenous fibrosis characteristic of constrictive pericarditis without evidence of malignancy or granulomatous disease. Pericardial cultures were negative for bacteria, viruses, fungi, and mycobacteria.

Figure 1

DISCUSSION

Constrictive pericarditis is characterized by chronic fibrous thickening of the once‐elastic pericardial sac and can occur following any disease process that affects the pericardium (Table 1).1, 2 The challenge in the diagnosis of constrictive pericarditis lies in the recognition of this slowly progressive and uncommon disease. In many cases, nonspecific symptoms of reduced cardiac output and insidious right‐sided heart failure are present for 12 months or longer before a diagnosis is established.1, 3 A typical presentation of constrictive pericarditis is peripheral edema, ascites, and hepatomegaly, a combination that may understandably lead to a misdiagnosis of chronic liver disease and even subject a patient to the unnecessary risk of a liver biopsy, as in this case.

Cryptogenic cirrhosis, the initial diagnosis of this patient, is a term used only after excluding the common and uncommon causes of cirrhosis (Table 2).46 With expanded knowledge of the causes of cirrhosis, especially nonalcoholic fatty liver disease, the number of cases of cirrhosis considered to be cryptogenic has decreased from nearly one‐third of all cases in 1960 to approximately 5% in a modern series.7, 8 Chronic or repetitive heart failure can lead to progressive hepatic fibrosis and cirrhosis. Distinguishing features compared to other causes of cirrhosis include an ascitic protein concentration greater than 2.5 g/dL, relatively preserved synthetic function, and infrequent stigmata of end‐stage liver disease such as spider angiomata or pronounced jaundice.9, 10

A key exam feature that distinguishes cardiac cirrhosis from other causes of liver failure is an elevated jugular venous pressure. Hepatic causes of cirrhosis induce increased nitric oxide production, which leads to splanchnic and peripheral arterial vasodilatation with a reduced effective circulating volume and normal or low jugular venous pressure.11, 12 Therefore, a patient with cirrhosis and ascites having an elevated jugular venous pressure should prompt echocardiographic evaluation.13 When echocardiography excludes ventricular dysfunction, valvular abnormalities, and pulmonary hypertension, constrictive pericarditis and restrictive cardiomyopathy remain important diagnostic considerations.

In both constrictive pericarditis and restrictive cardiomyopathy, ventricular filling is limited. Pressures in the chambers rise abruptly and rapidly during ventricular filling until equilibrium is reached in early diastole. This can be conceptualized as the cardiac chambers being constrained by the limitations of a rigid external box. In constrictive pericarditis, the rigid external box is the fibrosed and thickened pericardial sac, which loses its elasticity and impairs filling of the ventricles. In restrictive cardiomyopathy, the stiff myocardium limits ventricular filling.

There is considerable overlap in the clinical, echocardiographic, and hemodynamic findings of constrictive pericarditis and restrictive cardiomyopathy.14 Both may present insidiously with progressive heart failure. Echocardiography demonstrates impaired diastolic function. Cardiac hemodynamics demonstrate abrupt and rapid early diastolic filling, elevated and equal ventricular end‐diastolic pressures, and reduced stroke volume and cardiac output. A diagnosis of constrictive pericarditis is favored when a marked inspiratory increase in right ventricular pressures and decrease in left ventricular pressures are seen on heart catheterization or a similar inspiratory increase in transvalvular flow velocities across the tricuspid valve compared with the mitral valve is shown by echocardiography. This finding results from normal inspiratory increases in intrathoracic pressures, which are unable to be transmitted through the rigid pericardium but continue to augment venous return to the right side of the heart. As many as one‐third of patients with pericardial constriction lack these characteristic findings on echocardiogram.14

The results of pericardial imaging may suggest a diagnosis of constrictive pericarditis. Lateral chest radiography demonstrates pericardial calcifications in less than 30% of cases.15 Cardiac computed tomography (CT) and MRI are the best imaging modalities for detecting an increase in pericardial thickness (3 mm or greater).16 However, in as many as 20% of patients with surgically confirmed constrictive pericarditis, CT and MRI will demonstrate a pericardium of normal thickness.17

When faced with the diagnostic conundrum of constrictive pericarditis versus restrictive cardiomyopathy, strong clinical suspicion, thorough echocardiography, careful hemodynamic assessment with right and left heart catheterization,14, 18 pericardial imaging, and sometimes endomyocardial biopsy to exclude restrictive cardiomyopathy are often needed before proceeding to pericardiectomy, which carries a significant surgical risk but can also be curative.

This case highlights many of the features of constrictive pericarditis, the challenges and delay in its diagnosis, and its occasional misdiagnosis as chronic liver disease. Clinicians may recognize the typical combination of cirrhosis (or suspected cirrhosis), high SAAG ascites, and edema as characteristic of advanced intrinsic liver disease. However, they must not be seduced into immediate pattern recognition when contrary evidencesuch as elevated neck veins, elevated ascitic total protein, or relatively preserved hepatic synthetic functionaccompanies that picture. Under such circumstances, they must remember to think outside the box and bear in mind that the heart may be trapped inside a box.

A 65‐year‐old man was referred for evaluation of worsening ascites and end‐stage liver disease. The patient had been well until 1 year ago, when he developed lower extremity edema and abdominal distention. After evaluation by his primary care physician, he was given a diagnosis of cryptogenic cirrhosis. He underwent several paracenteses and was placed on furosemide and spironolactone. The patient had been stable on his diuretic regimen until 2 weeks previously, when he suddenly developed worsening edema and ascites, along with dizziness, nausea, and hypotension. His physician stopped the diuretics and referred him to the hospital.

Before diagnosing a patient with cryptogenic cirrhosis, it is necessary to exclude common etiologies of cirrhosis such as alcohol, viral hepatitis, and non‐alcoholic fatty liver disease and numerous uncommon causes, including Wilson's disease, hemochromatosis, Budd‐Chiari, and biliary cirrhosis. It is also important to remember that patients with liver disease are not immune to extrahepatic causes of ascites, such as peritoneal carcinomatosis and tuberculous ascites. Simultaneously, reasons for chronic liver disease decompensating acutely must be considered: medication nonadherence, excess salt intake, hepatotoxicity from acetaminophen or alcohol, and other acute insults, such as hepatocellular carcinoma, an intervening infection (especially spontaneous bacterial peritonitis), ascending cholangitis, or a flare of chronic viral hepatitis.

Past medical and surgical history included diabetes mellitus (diagnosed 10 years previously), obstructive sleep apnea, hypertension, hypothyroidism, and mild chronic kidney disease. Medications included levothyroxine, lactulose, sulfamethoxazole, pioglitazone (started 4 months prior), and ibuprofen. Furosemide and spironolactone had been discontinued 2 weeks previously. He currently resided in the Central Valley of California. He had lived in Thailand from age 7 to 17 and traveled to India more than 1 year ago. He did not smoke and had never used intravenous drugs or received a blood transfusion. He rarely drank alcohol. He worked as a chemist. There was no family history of liver disease.

There is no obvious explanation for the underlying liver disease or the acute decompensation. Sulfamethoxazole is a rare cause of allergic or granulomatous hepatitis. Pioglitazone is a thiazolinedione which in earlier formulations was linked to hepatitis but can be excluded as a cause of this patient's cirrhosis because it was started after liver disease was detected. As a chemist, he might have been exposed to carbon tetrachloride, a known hepatotoxin. Obstructive sleep apnea causes pulmonary hypertension, but severe ascites and acute hepatic decompensation would be unusual. Ibuprofen might precipitate worsening renal function and fluid accumulation. Time in Thailand and India raises the possibility of tuberculous ascites.

The patient had no headache, vision changes, abdominal pain, emesis, melena, hematochezia, chest pain, palpitations, dysuria, polyuria, pruritus, dark urine, or rashes. He reported difficulty with concentration when lactulose was decreased. He noted worsening exercise tolerance with dyspnea after 10 steps and reported a weight gain of 12 pounds in the past 2 weeks.

On examination, temperature was 36.8C; blood pressure, 129/87 mm Hg; heart rate, 85 beats per minute; respirations, 20 per minute; and oxygen saturation, 94% on room air. He was uncomfortable but alert. There was no scleral icterus or conjunctival pallor. Jugular venous pressure was elevated. The lungs were clear, and the heart was regular, with no murmur, rub, or gallops. The abdomen was massively distended with a fluid wave; the liver and spleen could not be palpated. There was pitting edema of the sacrum and lower extremities. There was no asterixis, palmar erythema, spider angiomata, or skin discoloration.

The additional history and physical exam suggest that the primary problem may lie outside the liver, especially as signs of advanced liver disease (other than ascites) are absent. Dyspnea on exertion is consistent with the physical stress of a large volume of ascites or could be secondary to several pulmonary complications associated with liver disease, including portopulmonary hypertension, hepatopulmonary syndrome, or hepatic hydrothorax. Alternatively, the dyspnea raises the possibility that the ascites is not related to a primary liver disorder but rather to anemia or to a cardiac disorder, such as chronic left ventricular failure, isolated right‐sided heart failure, or constrictive pericarditis. These diagnoses are suggested by the elevated jugular venous pressure, which is atypical in cirrhosis.

Although portal hypertension accounts for most cases of ascites, peritoneal fluid should be examined to exclude peritoneal carcinomatosis and tuberculous ascites. I am interested in the results of an echocardiogram.

Initial laboratory studies demonstrated a sodium concentration of 136 mEq/dL; potassium, 4.7 mEq/dL; chloride, 99 mEq/dL; bicarbonate, 24 mEq/dL; blood urea nitrogen, 54 mg/dL; creatinine, 3.3 mg/dL (increased from baseline of 1.6 mg/dL 4 months previously); white cell count, 7000/mm³; hemoglobin, 10.5 g/dL; MCV, 89 fL; platelet count, 205,000/mm³; bilirubin, 0.6 mg/dL; aspartate aminotransferase, 15 U/L; alanine aminotransferase, 8 U/L; alkaline phosphatase, 102 U/L; albumin, 4.2 g/dL; total protein, 8.2 g/dL; international normalized ratio, 1.2; and partial thromboplastin time, 31.8 seconds. A urine dipstick demonstrated 1+ protein. The chest radiograph was normal. Electrocardiogram had borderline low voltage with nonspecific T‐wave abnormalities. Additional studies showed a serum iron concentration of 49 mg/dL, transferrin saturation of 16%, total iron binding capacity of 310 mg/dL, and ferritin of 247 mg/mL. Hemoglobin A1c was 7.0%. Acute and chronic antibodies to hepatitis A, B, and C viruses were negative. The following study results were normal or negative: antinuclear antibody, alpha‐1‐antitrypsin, ceruloplasmin, alpha‐fetoprotein, carcinoembryonic antigen, and 24‐hour urinary copper. The thyroid function studies were normal. A purified protein derivative (PPD) skin test was nonreactive.

There continues to be a paucity of evidence of a primary liver disorder. The hepatic enzymes and tests of liver synthetic function are normal, and there is no pancytopenia, as might result from hypersplenism. I remain most suspicious of either a primary cardiac or pericardial disorder with secondary hepatic congestion or a disease that simultaneously affects the heart and liver.

The reasons for the low voltage on the electrocardiogram include processes that infiltrate the myocardium (amyloidosis, sarcoidosis, hemochromatosis, and myxedema fluid) and processes that increase the distance between the myocardium and surface electrodes, such as adipose tissue, air (from emphysema or pneumothorax), or pericardial effusion. Pericardial effusion may present subacutely with predominant features of right ventricular failure. Low voltage, liver disease, and possible heart failure raise the possibility of amyloidosis or hemochromatosis. The low transferrin saturation renders hemochromatosis unlikely. Although normal alkaline phosphatase and serum albumin are not characteristic when AL amyloid affects the liver and kidneys, serum and urine protein electrophoresis and immunofixation should be considered.

With paracentesis 3.5 L of ascitic fluid was removed. The red cell count was 4000/mm³, and white blood cell count was 505/mm³, of which 25% were polymorphonuclear cells, 22% were lymphocytes, and 53% were monocytes. Additional peritoneal fluid chemistries included albumin of 3.0 g/dL and total protein of 5.3 g/dL. Abdominal ultrasound with Doppler demonstrated a liver of normal size and echogenicity with patent hepatic arteries, hepatic veins, and portal vein. There was mild splenomegaly with normal kidneys. Evaluation for a possible liver transplant was initiated. Blood, urine, and peritoneal fluid cultures demonstrated no growth. Echocardiography demonstrated borderline concentric left ventricular hypertrophy, normal right and left ventricular function, dilated superior and inferior vena cavae, and no pericardial effusion or thickening.

The serum‐ascites albumin gradient (SAAG) of 1.2 is consistent with portal hypertension as the cause of the ascites. The Doppler findings exclude postsinusoidal causes of portal hypertension from hepatic vein obstruction or thrombosis. The combination of the elevated SAAG, elevated jugular venous pressure, borderline low voltage on ECG, and elevated peritoneal total protein make cardiac and pericardial disease the leading considerations. Given the normal ventricular function, I am concerned about elevated intracardiac pressures resulting from pericardial disease or restrictive cardiomyopathy. At this point, right heart catheterization would be useful for assessing intracardiac pressures.

On the fourth hospital day, paracentesis was repeated, and 15 L of fluid was removed. A transjugular liver biopsy demonstrated diffuse patchy fibrosis consistent with early cirrhosis and minor intralobular changes with minimal ballooning. There was no steatosis, active inflammation, granulomata, iron deposition, or evidence of viral hepatitis. Right heart catheterization revealed a right atrial pressure of 18 cm H₂0, right ventricular pressure of 34/20 cm H₂0, pulmonary artery pressure of 34/18 cm H₂0 (mean 25), pulmonary capillary wedge pressure of 20 cm H₂0, cardiac output of 5.8 L/min, and cardiac index of 2.5 L/min/m².

The mild hepatic histologic abnormalities do not support an intrinsic liver disease as the cause of his massive ascites and end‐stage liver disease physiology. Cardiac catheterization demonstrates equalization of diastolic pressures, which suggests constrictive pericarditis or restrictive cardiomyopathy. Despite the normal chest radiograph and nonreactive PPD, tuberculosis would be my leading explanation for constrictive pericarditis given the time spent in areas endemic with TB. Although lateral chest radiography may demonstrate pericardial calcifications, magnetic resonance imaging (MRI) is the best imaging modality to detect constrictive pericarditis. Alternately, cardiac amyloidosis could cause restrictive cardiomyopathy and has not been definitively excluded. A cardiac MRI to assess the pericardium would be my next test, and I would request Congo red stains of the liver biopsy. If these tests are unrevealing, endomyocardial biopsy may be necessary.

The cardiac MRI revealed a severely thickened 7‐mm pericardium (normal < 3 mm) most prominent over the right atrium and ventricle. The right ventricle was described as bullet‐shaped, suggesting constrictive pericardial disease (Fig. 1). Left heart catheterization to evaluate coronary anatomy and left ventricular pressures revealed no significant coronary arterial disease and demonstrated an elevated left ventricular end‐diastolic pressure consistent with constrictive pericarditis. Endomyocardial biopsy showed no evidence of infiltrative disease, granulomata, or other significant abnormality. The following day the patient underwent pericardiectomy. Postoperatively, his ascites was easily managed with low doses of diuretics. The pericardial tissue revealed chronic inflammatory cells and dense collagenous fibrosis characteristic of constrictive pericarditis without evidence of malignancy or granulomatous disease. Pericardial cultures were negative for bacteria, viruses, fungi, and mycobacteria.

Figure 1

DISCUSSION

Constrictive pericarditis is characterized by chronic fibrous thickening of the once‐elastic pericardial sac and can occur following any disease process that affects the pericardium (Table 1).1, 2 The challenge in the diagnosis of constrictive pericarditis lies in the recognition of this slowly progressive and uncommon disease. In many cases, nonspecific symptoms of reduced cardiac output and insidious right‐sided heart failure are present for 12 months or longer before a diagnosis is established.1, 3 A typical presentation of constrictive pericarditis is peripheral edema, ascites, and hepatomegaly, a combination that may understandably lead to a misdiagnosis of chronic liver disease and even subject a patient to the unnecessary risk of a liver biopsy, as in this case.

Cryptogenic cirrhosis, the initial diagnosis of this patient, is a term used only after excluding the common and uncommon causes of cirrhosis (Table 2).46 With expanded knowledge of the causes of cirrhosis, especially nonalcoholic fatty liver disease, the number of cases of cirrhosis considered to be cryptogenic has decreased from nearly one‐third of all cases in 1960 to approximately 5% in a modern series.7, 8 Chronic or repetitive heart failure can lead to progressive hepatic fibrosis and cirrhosis. Distinguishing features compared to other causes of cirrhosis include an ascitic protein concentration greater than 2.5 g/dL, relatively preserved synthetic function, and infrequent stigmata of end‐stage liver disease such as spider angiomata or pronounced jaundice.9, 10

A key exam feature that distinguishes cardiac cirrhosis from other causes of liver failure is an elevated jugular venous pressure. Hepatic causes of cirrhosis induce increased nitric oxide production, which leads to splanchnic and peripheral arterial vasodilatation with a reduced effective circulating volume and normal or low jugular venous pressure.11, 12 Therefore, a patient with cirrhosis and ascites having an elevated jugular venous pressure should prompt echocardiographic evaluation.13 When echocardiography excludes ventricular dysfunction, valvular abnormalities, and pulmonary hypertension, constrictive pericarditis and restrictive cardiomyopathy remain important diagnostic considerations.

In both constrictive pericarditis and restrictive cardiomyopathy, ventricular filling is limited. Pressures in the chambers rise abruptly and rapidly during ventricular filling until equilibrium is reached in early diastole. This can be conceptualized as the cardiac chambers being constrained by the limitations of a rigid external box. In constrictive pericarditis, the rigid external box is the fibrosed and thickened pericardial sac, which loses its elasticity and impairs filling of the ventricles. In restrictive cardiomyopathy, the stiff myocardium limits ventricular filling.

There is considerable overlap in the clinical, echocardiographic, and hemodynamic findings of constrictive pericarditis and restrictive cardiomyopathy.14 Both may present insidiously with progressive heart failure. Echocardiography demonstrates impaired diastolic function. Cardiac hemodynamics demonstrate abrupt and rapid early diastolic filling, elevated and equal ventricular end‐diastolic pressures, and reduced stroke volume and cardiac output. A diagnosis of constrictive pericarditis is favored when a marked inspiratory increase in right ventricular pressures and decrease in left ventricular pressures are seen on heart catheterization or a similar inspiratory increase in transvalvular flow velocities across the tricuspid valve compared with the mitral valve is shown by echocardiography. This finding results from normal inspiratory increases in intrathoracic pressures, which are unable to be transmitted through the rigid pericardium but continue to augment venous return to the right side of the heart. As many as one‐third of patients with pericardial constriction lack these characteristic findings on echocardiogram.14

The results of pericardial imaging may suggest a diagnosis of constrictive pericarditis. Lateral chest radiography demonstrates pericardial calcifications in less than 30% of cases.15 Cardiac computed tomography (CT) and MRI are the best imaging modalities for detecting an increase in pericardial thickness (3 mm or greater).16 However, in as many as 20% of patients with surgically confirmed constrictive pericarditis, CT and MRI will demonstrate a pericardium of normal thickness.17

When faced with the diagnostic conundrum of constrictive pericarditis versus restrictive cardiomyopathy, strong clinical suspicion, thorough echocardiography, careful hemodynamic assessment with right and left heart catheterization,14, 18 pericardial imaging, and sometimes endomyocardial biopsy to exclude restrictive cardiomyopathy are often needed before proceeding to pericardiectomy, which carries a significant surgical risk but can also be curative.

This case highlights many of the features of constrictive pericarditis, the challenges and delay in its diagnosis, and its occasional misdiagnosis as chronic liver disease. Clinicians may recognize the typical combination of cirrhosis (or suspected cirrhosis), high SAAG ascites, and edema as characteristic of advanced intrinsic liver disease. However, they must not be seduced into immediate pattern recognition when contrary evidencesuch as elevated neck veins, elevated ascitic total protein, or relatively preserved hepatic synthetic functionaccompanies that picture. Under such circumstances, they must remember to think outside the box and bear in mind that the heart may be trapped inside a box.