Case 36-2007 — A 31-Year-Old Woman with Rash, Fever, and Hypotension

Presentation of Case

Dr. Jeffrey O. Greenberg (Medicine): A 31-year-old woman was admitted to this hospital because of facial swelling, fever, and hypotension.

The patient had relapsing and remitting multiple sclerosis, associated with severe fatigue. Three weeks before admission, her neurologist prescribed modafinil to treat the fatigue. One week later, periorbital erythema, a clear conjunctival discharge, and a raised erythematous and pruritic rash developed on her face and scalp. She discontinued modafinil and used over-the-counter diphenhydramine, but the rash did not improve. Three days later, she went to the emergency room of a hospital near her home for evaluation. Cyproheptadine was prescribed, but the pharmacy dispensed perphenazine in error. Two days later, she was reevaluated at the same facility; the medication error was noted, and prednisone (60 mg) and cyproheptadine were begun. The facial rash improved transiently, but 5 days before admission, it recurred, and similar lesions developed on her back and chest.

On examination by a physician at this hospital the next day, there was swelling around the eyes, nose, and left ear, and an urticarial rash on the torso. Cyproheptadine was stopped, and diphenhydramine and ranitidine were added. During the next 2 days, painful swelling under the left mandible and pain in the hips developed, and facial swelling and erythema near the left eye increased. She returned to the hospital near her home and was given doxycycline for possible cellulitis of the face. The day before admission, increased facial swelling with discomfort in the left ear, blurred vision, pelvic pain, and dysuria had developed and she returned to the emergency department of that hospital.

She appeared anxious. The temperature was 37.5°C, the blood pressure 131/74 mm Hg, the pulse 148 beats per minute, and the oxygen saturation 96% while she was breathing ambient air. There was a maculopapular facial rash and swelling of the face, left parotid gland, and left external auditory canal, with bilateral cervical lymphadenopathy. Levels of serum glucose and electrolytes and tests of liver and renal function were normal; results of other laboratory tests are shown in Table 1. Ninety minutes after arrival, meperidine and promethazine were administered, followed by diphenhydramine and famotidine. Shortly thereafter, she reported lightheadedness; the blood pressure was transiently 70/40 mm Hg, and the temperature 38.5°C. Electrocardiography showed borderline sinus tachycardia and mild right-axis deviation. Clindamycin, prednisone, and additional diphenhydramine were administered, followed by acetaminophen and hydrocodone. Approximately 18 hours after arrival, she was transferred to the emergency department of this hospital for otolaryngologic evaluation of the facial and neck swelling.

View this table: [in this window] [in a new window] Table 1. Results of Laboratory Tests.

Multiple sclerosis had been diagnosed 4 years earlier during an episode of optic neuritis; a hyperintense lesion consistent with a plaque was seen on magnetic resonance imaging (MRI). Her symptoms included blurred vision, tingling and weakness in the left leg and arm, and extreme fatigue. Methylprednisolone infusions were given intermittently for exacerbations. Other medications in the past had included copaxone, amantadine, and daclizumab.

She had bipolar disorder, which was being treated with sertraline and oxcarbazepine. Electrocardiograms (ECGs) and echocardiograms were normal 2 years before admission. She was allergic to amoxicillin and doxycycline, which had caused gastrointestinal distress, blurred vision, and a rash. She lived with her husband and child, smoked 5 to 10 cigarettes daily, drank alcohol rarely, and did not use illicit drugs. There was a family history of coronary artery disease, hypertension, and bipolar disorder, and an aunt had systemic lupus erythematosus.

On examination, the blood pressure was 118/70 mm Hg, the pulse 135 beats per minute, and the temperature 38.9°C; the respirations were 20 breaths per minute, and the oxygen saturation was 99% while she was breathing ambient air. She appeared ill. The physical examination was unchanged. Results of laboratory tests are shown in Table 1; specimens of blood were sent for culture. Computed tomographic (CT) scans of the neck showed a mass, 2 cm in diameter in the inferior left masseter muscle near the angle of the jaw, enlarged cervical lymph nodes, and acute and chronic sinusitis. An ECG revealed sinus tachycardia at a rate of 120 beats per minute and nonspecific ST-segment and T-wave abnormalities. Radiographs of the pelvis and chest were normal. Vancomycin, levofloxacin, clindamycin, and stress-dose corticosteroids were administered.

The next morning, 21 hours after arrival in the emergency department, she reported chest tightness, worse with inspiration. An electrocardiogram (Figure 1 in the Supplementary Appendix, available with the full text of this article at www.nejm.org) showed sinus tachycardia at 112 beats per minute and ST-segment elevation of 1 to 2 mm in leads I, aVL, V₄, and V₅. Results of laboratory tests are shown in Table 1. Heparin and metoprolol were administered intravenously. The blood pressure fell to 92/53 mm Hg and then to 71/30 mm Hg, and dopamine and saline were infused intravenously. Transthoracic echocardiography revealed mild left ventricular dysfunction with inferior and septal wall-motion abnormalities, a left ventricular ejection fraction of 43%, and a small pericardial effusion with partial right atrial inversion. She was admitted to the cardiac intensive care unit 28 hours after arrival in the emergency department.

On arrival in the intensive care unit, the blood pressure was 149/119 mm Hg, with a pulsus paradoxus of 7 mm Hg, the pulse 135 beats per minute, and the temperature 38.5°C; the respirations were 20 breaths per minute, and the arterial oxygen saturation was 97% while the patient was breathing 6 liters of oxygen by nasal cannula. Crackles were heard over both lung bases. The jugular venous pressure was 11 cm of water; there was no Kussmaul's sign, and no extra heart sounds were heard. The arms and legs were warm, with no edema. An ECG showed sinus tachycardia at 140 beats per minute and diffuse ST-segment elevation of 1 mm or more in leads I, aVL, V₂ through V₆, and II.

The next morning, a chest radiograph showed perihilar pulmonary edema. The heart and mediastinum were normal. Repeated transthoracic echocardiography showed deterioration of left ventricular function, with an ejection fraction of 32%, increased thickness of the left ventricular wall, right ventricular dysfunction, a small circumferential pericardial effusion, right atrial and right ventricular inversions, and marked respiratory variations of the mitral and tricuspid inflow according to Doppler signals. The patient was taken to the cardiac catheterization laboratory, and a pulmonary arterial line was placed; mean right atrial, right ventricular end-diastolic, and mean pulmonary capillary wedge pressures were 20 to 25 mm Hg. The cardiac output was 2.2 liters per minute. Pericardiocentesis was performed, revealing a mean pericardial pressure of 23 mm Hg. After 150 ml of pink, slightly turbid fluid was aspirated, the cardiac output rose to 3.3 liters per minute. Coronary angiography revealed no stenoses.

The aspirated fluid contained 1530 white cells per cubic millimeter, with 63% eosinophils; the protein level was 4.5 g per deciliter, the amylase level was 21 U per liter, and the lactic dehydrogenase level was 744 U per liter. A Gram's stain revealed no microorganisms. Solumedrol (1 g daily) was started intravenously.

The same day, pathological examination of a fine-needle aspiration of the mass in the left jaw revealed skeletal muscle with mixed inflammatory cells, including eosinophils; flow cytometry disclosed polyclonal CD19+ B cells and CD4+ and CD8+ T cells. Serum protein electrophoresis and levels of immunoglobulins were normal, a test for antinuclear antibodies was positive at a titer of 1:40 in a speckled pattern, and other autoantibody testing was negative. Other test results are shown in Table 1.

On the fourth hospital day, a chest radiograph showed increased pulmonary edema. Another transthoracic echocardiogram showed no pericardial effusion, but there was further decline of function of both ventricles, with a left ventricular ejection fraction of 16%.

A diagnostic procedure was performed.

Differential Diagnosis

Dr. Marc S. Sabatine: May we review the imaging studies?

Dr. Jo-Anne O. Shepard: A CT scan of the facial bones and neck (Figure 1A), performed after the intravenous administration of contrast material, showed a rounded opacity with peripheral enhancement in the left masseter muscle, with central necrosis, which was suspicious for a small abscess, and left cervical lymphadenopathy. On the second hospital day, perihilar interstitial pulmonary edema was evident on chest radiographs (Figure 1B); the edema increased by day 4. The heart size remained normal, despite the presence of a small pericardial effusion.

View larger version (49K): [in this window] [in a new window] Figure 1. Radiologic Images. A CT scan of the facial bones and neck on the first hospital day (Panel A) shows a rounded opacity with peripheral enhancement and central necrosis in the left submandibular region, which suggested a small abscess (arrow). A chest radiograph on the second hospital day (Panel B) reveals perihilar pulmonary edema

Dr. Kian-Keong Poh: The first transthoracic echocardiogram shows mild left ventricular systolic dysfunction with hypokinesia of the inferior and septal walls and a small circumferential pericardial effusion resulting in right atrial inversion. The next day, there was increased left ventricular wall thickness and a further decrease in left ventricular systolic function, right ventricular systolic dysfunction with persistence of the pericardial effusion, and right atrial collapse (Figure 2A, and Video 1 in the Supplementary Appendix). Pulsed-wave Doppler studies of the mitral inflow (Figure 2B) and tricuspid inflow and aortic outflow showed clinically significant respiratory variations, consistent with increased intrapericardial pressure.

View larger version (42K): [in this window] [in a new window] Figure 2. Echocardiographic Images. A transthoracic echocardiogram (Panel A) on the second hospital day at the apical four-chamber window shows a small pericardial effusion (PE) and right atrial inversion (arrow). LA denotes left atrium, RA right atrium, LV left ventricle, and RV right ventricle. A pulsed-wave Doppler echocardiogram (Panel B) shows significant respiratory variation of the transmitral flow velocities, with a decrease in inspiration.

Dr. Jessica L. Mega: Cardiac catheterization showed an elevated right atrial pressure of 22 mm Hg, a right ventricular end-diastolic pressure of 22 mm Hg, and a mean pulmonary-capillary wedge pressure of 25 mm Hg (Fig. 2 in the Supplementary Appendix). The pericardial pressure was elevated, at 23 mm Hg, equal to the mean right atrial pressure (Fig. 3A in the Supplementary Appendix). In addition, there was marked variation in the aortic pressure tracing with respirations (Fig. 3B in the Supplementary Appendix). After fluid was aspirated from the pericardial space, the pericardial pressure was 10 mm Hg and the aortic pressure tracing normalized (Fig. 3C and 3D in the Supplementary Appendix). Before the procedure, the cardiac index was 1.3 liters per minute per square meter of body-surface area, with a stroke volume index of 9 ml per square meter. After the procedure, the cardiac index improved to 1.9 liters per minute per square meter, with a stroke volume index of 16 ml per square meter.

Dr. Poh: Echocardiography performed 1 day after the pericardial drainage revealed no pericardial effusion. However, the left and right ventricular functions had deteriorated further; in particular, the left ventricle showed diffuse and severe involvement, with hypokinesia in all walls. The left ventricular ejection fraction was 16%, contributed mainly by its base (Video 2 in the Supplementary Appendix). There was echocardiographic documentation of a rapidly progressive process over a few days, resulting in biventricular failure.

Dr. Sabatine: I participated in this patient's care and am aware of the diagnosis. Three weeks before this 31-year-old woman presented to this hospital, periorbital erythema, a conjunctival discharge, and a pruritic facial rash developed after she had started taking modafinil. Despite treatment with antihistamines and corticosteroids, her symptoms persisted. At another hospital, a low-grade fever, left facial swelling, and transient hypotension were noted. She was transferred here for evaluation of a possible facial abscess. However, her course took an unexpected turn when chest pain developed, and she was found to have ST-segment elevation and elevated cardiac biomarkers of necrosis. Although initially there was concern about an acute coronary syndrome, the patient's sex and age, the diffuse nature of the ST-segment elevation, the relatively minor degree of elevation of biomarkers, and the mild diffuse left ventricular dysfunction that did not match the ECG changes all pointed to myopericarditis.

There were several early clues to the severity of this patient's hemodynamic compromise. Hypotension that developed in response to treatment with a beta-blocker showed that she was dependent on sympathetically mediated increases in heart rate and contractility to maintain blood pressure. This finding suggests a greatly reduced stroke volume, most commonly seen in cases of hypovolemic shock. Yet after aggressive fluid resuscitation, although her blood pressure returned to normal, she had a narrow pulse pressure, consistent with a low stroke volume. This observation, coupled with elevated jugular venous pulsations and crackles over the lung fields, suggested profound myocardial dysfunction caused by impaired contractility, pericardial tamponade, or, as it turns out in this case, both.

Although the list of cardiomyopathies is extensive, the rapid deterioration of systolic function in this patient suggests an acute myocarditis. Another possibility that was briefly considered was cardiac involvement by a sarcoma or a lymphoma because of her fever, soft-tissue mass, and cervical lymphadenopathy. However, myocardial involvement by tumor typically presents with restrictive physiology and arrhythmias, rather than with rapidly progressive systolic dysfunction, and neither fine-needle aspiration of the mass nor cytologic examination of the pericardial fluid revealed malignant tumor.

Infectious Myocarditis

Several forms of myocarditis merit consideration in this case.¹ Viral myocarditis is often preceded by a viral prodrome, although this finding is neither sensitive nor specific. Presentations range from slow development of heart failure to rapid development of cardiogenic shock. The ECG often shows nonspecific ST-segment and T-wave abnormalities; echocardiographic findings range from a nondilated left ventricle seen in the acute phase to a spherical, dilated left ventricle in the chronic phase. This patient's presentation is best described as fulminant myocarditis, which has a distinct onset, a nondilated and thickened left ventricle, and severe systolic dysfunction leading to cardiogenic shock.² Patients either recover spontaneously or die.³ Bacterial myocarditis was a possibility in this patient because of her possible abscess. However, one would have expected a purulent pericardial fluid and distributive shock requiring vasopressors. Lyme disease can manifest with rash and myocarditis, but the latter is usually mild. Rickettsial disease presents with rash, fever, hypotension, and only a mild myocarditis.

Autoimmune Myocarditis

Autoimmune myocarditides should be considered in this young woman with an autoimmune disorder (multiple sclerosis), a rash, and a family history of systemic lupus erythematosus. Both systemic lupus erythematosus and polymyositis can be associated with pericarditis and myocarditis, but the myocarditis tends to be mild. This patient did not have rheumatologic, dermatologic, or serologic manifestations of those disorders.

Idiopathic Isolated Giant-Cell Myocarditis

Idiopathic giant-cell myocarditis is a fulminant disease that typically affects persons in their fourth and fifth decades.⁴ Approximately 20% of patients have an autoimmune disorder, although giant-cell myocarditis has not been described in association with multiple sclerosis. Patients often report antecedent symptoms of a viral upper respiratory tract infection, and chest pain is uncommon. Symptoms of heart failure develop over a period of weeks to months, with a rapid deterioration of cardiac function during the final stages of the disease. Conduction-system disease and ventricular tachycardia may occur because of infiltration of the fascicles and myocardium, but ST-segment elevation is extremely rare. On echocardiography, left ventricular dilatation without hypertrophy is seen, with segmental or diffuse areas of hypokinesis. The pericardial effusion with eosinophils, the chest pain, and the ST-segment elevation seen in this patient are not typical features of idiopathic giant-cell myocarditis.

Eosinophilic Cardiomyopathies

Eosinophilic cardiomyopathies include a range of clinical presentations and pathological findings (Table 2). Löffler's endocarditis⁵ is a restrictive cardiomyopathy due to endomyocardial disease with mural thrombi (so-called thrombotic endocarditis) and is secondary to eosinophilia from many causes. Endomyocardial fibrosis⁶ is a restrictive cardiomyopathy affecting persons in tropical climates in whom peripheral eosinophilia is inconsistent. In both these disorders, which probably represent a continuum,⁷ the disease typically develops gradually over a period of months to years. In contrast, this patient had a rapid decline in left ventricular function.

View this table: [in this window] [in a new window] Table 2. Eosinophilic Cardiomyopathies.

Acute Eosinophilic Myocarditis

Acute eosinophilic myocarditis (also known as hypersensitivity myocarditis) is caused by a drug hypersensitivity reaction⁸ and is characterized by fever, rash, peripheral eosinophilia, and elevated biomarkers of necrosis.⁹ ECG occasionally shows ST-segment elevation. Echocardiography reveals mild systolic dysfunction, increased wall thickness due to edema, and occasionally a pericardial effusion. Heart failure is typically mild, and patients die of arrhythmias, rather than pump dysfunction.¹⁰ Many drugs have been implicated in acute eosinophilic myocarditis (Table 3),^9,10 including tetracyclines,¹⁰ carbamazepine,¹¹ and perphenazine.¹² When I saw this patient, I found no reports that associated modafinil with acute eosinophilic myocarditis. The time of onset after starting a drug varies from days to months. The incidence of acute eosinophilic myocarditis ranges from more than 40% of patients recently taking sulfonamides⁸ to less than 1% of patients taking clozapine.¹³

View this table: [in this window] [in a new window] Table 3. Medications Implicated in Hypersensitivity Myocarditis (Acute Eosinophilic Myocarditis and Acute Necrotizing Eosinophilic Myocarditis).

Acute Necrotizing Eosinophilic Myocarditis

A fulminant form of hypersensitivity myocarditis, called acute necrotizing eosinophilic myocarditis, presents with severe heart failure that develops within days to a week.^{14,15,16,17,18,19} Although initiation of a new medication is often the precipitant (especially in patients with a history of an allergic diathesis), cases occur in the setting of viral or parasitic infection, the Churg–Strauss syndrome, or the hypereosinophilic syndrome. Fever and rash are common. The presentation often mimics that of acute myocardial infarction, with chest pain, ST-segment elevation, and elevated biomarkers of necrosis.²⁰ Blood eosinophilia is present in most cases but can be mild. Echocardiography typically reveals normal chamber size (reflecting the sudden onset of the process and lack of time for dilatation), increased wall thickness (probably reflecting edema), and severe, biventricular diffuse systolic dysfunction. A pericardial effusion is seen in 75% of cases, occasionally causing tamponade.²¹ The mortality exceeds 50%, and the median survival is only a few days. Treatment consists of high-dose corticosteroids,^9,19,22 pharmacologic or mechanical ventricular support, or both.²³

Summary

In view of the tempo and severity of this patient's disease, I thought that the most likely diagnoses were fulminant viral myocarditis, idiopathic giant-cell myocarditis, and acute necrotizing eosinophilic myocarditis. The chest pain, ST-segment elevation, lack of conduction block, and presence of a pericardial effusion make idiopathic giant-cell myocarditis unlikely. The exposure to drugs associated with hypersensitivity myocarditis, the rash and fever, and the eosinophil-rich pericardial effusion favor acute necrotizing eosinophilic myocarditis over fulminant viral myocarditis. Since the treatment of these three diseases differs, a specific diagnosis is important. Histologic examination would most clearly differentiate these entities, and thus the diagnostic procedure was an endomyocardial biopsy.

Dr. Marc S. Sabatine's Diagnosis

Acute necrotizing eosinophilic myocarditis due to a hypersensitivity reaction.

Pathological Discussion

Dr. James R. Stone: Examination of the specimen from the endomyocardial biopsy revealed an extensive inflammatory infiltrate composed mostly of eosinophils and macrophages and associated with myocyte necrosis (Figure 3A). Immunohistochemical analysis showed that the lymphocytes were almost entirely CD3+ T cells, with a predominance of CD4+ over CD8+ cells (Fig. 4 in the Supplementary Appendix). There was no endocardial thickening or necrotizing vasculitis, nor were there any giant cells. Focally, the inflammatory infiltrate was associated with small interstitial vessels, a feature that has been referred to as non-necrotizing vasculitis. There was no viral cytopathic effect or intracellular parasites, and special stains for organisms were negative.

View larger version (82K): [in this window] [in a new window] Figure 3. Pathological Findings. Panel A (hematoxylin and eosin) shows an inflammatory infiltrate with associated myocyte necrosis. A higher-power view (Panel A, inset) shows the infiltrate to be composed primarily of eosinophils and macrophages, with fewer lymphocytes. A formalin-fixed cut section of the heart at autopsy (Panel B) shows the left ventricular free wall as viewed from a posterior perspective. The aortic valve is in the upper right corner. The left circumflex artery, at the upper edge of the panel, is free of clinically significant atherosclerosis. The left ventricular myocardium shows diffuse mottling indicative of necrosis. A section of the myocardium (Panel C, hematoxylin and eosin) shows an inflammatory infiltrate with associated myocyte necrosis in the bottom left corner, as it borders healthy myocardium in the upper right corner. A giant cell is present on the far left edge of the panel (arrow). A higher-power view of the edge of the inflammatory infiltrate (Panel C, inset, top) shows the infiltrate to be composed primarily of eosinophils and macrophages, with fewer lymphocytes. A higher-power view of the center of the zones of necrosis (Panel C, inset, bottom) shows the presence of macrophage giant cells engulfing necrotic myocyte debris. Microscopical examination of deep white matter reveals the presence of an area of demyelination with focal loss of myelin and relative axonal preservation (Panel D, arrows; axon stain not shown). A vessel with perivascular lymphocytic cuffing is evident as well (arrowhead). A higher-magnification view of the blood vessel illustrates the perivascular lymphocytic infiltrate; eosinophils are not present (Panel D, inset, Luxol fast blue–hematoxylin and eosin). Perivascular inflammation, consisting predominantly of lymphocytes, is present in the dorsal horn of the lumbar spinal cord (Panel E).

In the absence of evidence of infection, the histologic findings on the endomyocardial biopsy are that of an acute necrotizing eosinophilic myocarditis.^{16,18,19,24,25} In this patient, they are most likely a manifestation of a severe form of drug-induced hypersensitivity myocarditis.

Dr. Mega: At the time of the ventricular biopsy, an intraaortic balloon pump was placed because of deteriorating left ventricular function. The patient then returned to the cardiac care unit, and methylprednisolone (1 mg per day) was continued. Initially, her clinical status improved, and the dopamine dose was reduced. However, on the evening of the fourth hospital day, a refractory ventricular tachyarrhythmia developed, and she died. An autopsy was performed.

Dr. Stone: The heart was enlarged (468 g), with mild biventricular dilatation and a mottled appearance of the ventricular myocardium (Figure 3B, and Fig. 5 in the Supplementary Appendix), reflecting necrosis involving about 80% of the myocardium (Figure 3C). Around the outer portions of the zones of necrosis, there was an intense inflammatory infiltrate (Figure 3C, inset, top) consisting predominantly of eosinophils and macrophages, as observed in the endomyocardial biopsy. In the central portions of the necrotic zones, macrophage giant cells were present and were engulfing necrotic myocytes (Figure 3C, inset, bottom). As in the biopsy specimen, the T cells were predominantly CD4+ (Fig. 6 in the Supplementary Appendix). The wall of the coronary sinus, containing cardiac myocytes, also showed inflammatory infiltration and necrosis (Fig. 7 in the Supplementary Appendix). The inflammation in the heart extended into the epicardium, and there was focal eosinophilic vasculitis of the epicardial veins (Fig. 8 in the Supplementary Appendix). Stains of the myocardium for microorganisms were negative.

Skeletal muscle from the deltoid, diaphragm, and extraocular muscles showed similar changes (Fig. 8 in the Supplementary Appendix). Retrospective analysis of the fine-needle aspirate from the left masseter muscle revealed eosinophils, macrophages, and fragments of necrotic skeletal muscle and macrophage giant cells (Figure 9 in the Supplementary Appendix). In the liver, small zones of necrosis in a random distribution were seen to contain inflammatory cells, predominantly macrophages with lesser numbers of T cells and rare eosinophils (Fig. 10 in the Supplementary Appendix). There was no viral cytopathic effect, and in situ hybridization for Epstein–Barr virus RNA was negative.

These findings indicate the presence of a severe systemic necrotizing inflammatory reaction, associated with eosinophils and giant cells. Several systemic processes can result in giant cells in the heart, including sarcoidosis, acute rheumatic fever, rheumatoid disease, antineutrophil cytoplasmic antibody–associated vasculitides, and amyloidosis, as well as mycobacterial, parasitic, and fungal infections, none of which are present in this case. Both giant cells and eosinophils may be present in giant-cell myocarditis, hypersensitivity myocarditis, and acute necrotizing eosinophilic myocarditis.

Giant-cell myocarditis occurs in two distinct forms: idiopathic isolated giant-cell myocarditis and thymoma-associated giant-cell polymyositis. Idiopathic isolated giant-cell myocarditis is limited to the heart,^4,26 with infiltration of myocardium by lymphocytes, macrophages, giant cells, and eosinophils and marked necrosis, whereas in thymoma-associated giant-cell polymyositis, a similar inflammatory infiltrate involves both cardiac and skeletal muscles.^27,28 In giant-cell myocarditis, the T lymphocytes show a predominance of CD8+ over CD4+ staining,²⁹ and the giant cells are typically proximate to both viable and dead myocytes, suggesting that they have an active role in the killing of myocytes.

Hypersensitivity myocarditis is often defined as a histologic pattern in which there is infiltration of the myocardium by eosinophils, macrophages, and lymphocytes with minimal to no necrosis of myocytes.^8,9,10 When necrotizing drug-induced hypersensitivity reactions are found, names such as drug-induced acute necrotizing eosinophilic myocarditis^{16,18,19,24,25} or drug-induced giant-cell myocarditis have been used^30,31,32; however, these are probably the extreme end of the spectrum of hypersensitivity myocarditis. In cases of acute necrotizing eosinophilic myocarditis, as opposed to cases of giant-cell myocarditis, giant cells may be seen only in areas of necrotic myocytes, where they are engaged in the removal of opsonin-coated myocyte debris, and the T cells are predominantly CD4+.³³ Thus, this case has both morphologic and immunophenotypic features of acute necrotizing eosinophilic myocarditis. At autopsy, both necrotizing and non-necrotizing cases of drug-induced eosinophilic myocarditis may have extracardiac involvement, as was seen in this case; most commonly, the liver is involved, and on rare occasions other organs are involved, including the lung, the kidney, and skeletal muscle.^{8,9,10,30,31,32}

This patient died in 2006. Since then, the package insert for modafinil has been modified to include a warning relating to multiorgan hypersensitivity reactions.

Dr. Matthew P. Frosch: The brain and spinal cord were also examined. The plaques of multiple sclerosis that had been identified by imaging studies were confirmed by gross and microscopical examination of the brain, showing loss of myelin (Figure 3D) with relative axonal preservation. Although the plaques were chronic, there was moderate perivascular inflammation (Figure 3D, inset) consisting of T cells with a predominance of CD4+ cells (Fig. 11 in the Supplementary Appendix).

Inflammation was also present in the spinal cord, most prominently in the dorsal horn (Figure 3E), associated with gliosis but not demyelination. There was also inflammation in the leptomeninges and in the proximate portion of the peripheral nerve (Figure 12 in the Supplementary Appendix). Even though none of these lesions contained eosinophils, the distribution of the inflammatory process (both central and peripheral nervous systems) and the absence of associated active demyelination suggests that these represent involvement by the systemic necrotizing hypersensitivity reaction rather than a manifestation of multiple sclerosis.

Dr. Aaron Baggish (Cardiology Division): The cause of death in this patient was a malignant ventricular tachyarrhythmia in the context of clinically improving heart failure. Do you think there is a role for treating such patients with prophylactic antiarrhythmic therapy?

Dr. Sabatine: Extrapolating from the literature on myocardial infarction, pharmacologic arrhythmia prophylaxis does not appear to be beneficial; rather, patients should be monitored closely and arrhythmias treated immediately.

Anatomical Diagnosis

Acute necrotizing eosinophilic myocarditis associated with a systemic necrotizing inflammatory process also involving skeletal muscle, the liver, and the spinal cord, most consistent with a severe drug-induced hypersensitivity reaction.

Dr. Sabatine reports receiving research grants from Sanofi–Aventis and Schering-Plough, research reagents from Roche, diaDexus, and Singulex, and lecture and consulting fees from Bristol-Myers Squibb, Sanofi–Aventis, diaDexus Novartis, and Daiichi Sankyo; Dr. Mega, grant support from Schering-Plough; Dr. Shepard, consulting fees from R2 Technology; Dr. Stone, consulting fees from Merck, MuscleTech, GNC Corporation, and Wal-Mart; and Dr. Frosch, consulting fees from Biogenidec and Bristol-Myers Squibb. No other potential conflict of interest relevant to this article was reported.

Source Information

From the Cardiovascular Division, Brigham and Women's Hospital (M.S.S.); the Cardiology Division (M.S.S., K.-K.P., J.L.M.) and the Departments of Radiology (J.-A.O.S.) and Pathology (J.R.S., M.P.F.), Massachusetts General Hospital; and the Departments of Medicine (M.S.S., K.-K.P., J.L.M.), Radiology (J.-A.O.S.), and Pathology (J.R.S., M.P.F.), Harvard Medical School — all in Boston.

References

1. Feldman AM, McNamara D. Myocarditis. N Engl J Med 2000;343:1388-1398. [Free Full Text]
2. Lieberman EB, Hutchins GM, Herskowitz A, Rose NR, Baughman KL. Clinicopathologic description of myocarditis. J Am Coll Cardiol 1991;18:1617-1626. [Abstract]
3. Mason JW, O'Connell JB, Herskowitz A, et al. A clinical trial of immunosuppressive therapy for myocarditis. N Engl J Med 1995;333:269-275. [Free Full Text]
4. Cooper LT Jr, Berry GJ, Shabetai R. Idiopathic giant-cell myocarditis -- natural history and treatment. N Engl J Med 1997;336:1860-1866. [Free Full Text]
5. Löffler W. Endocarditis parietalis fibroplastica mit bluteosinophilie. Schweiz Med Wochenschr 1936;66:817-817.
6. Davies JNP. Endomyocardial fibrosis in Africans. East Afr Med J 1948;25:10-14.
7. Roberts WC, Liegler DG, Carbone PP. Endomyocardial disease and eosinophilia: a clinical and pathologic spectrum. Am J Med 1969;46:28-42. [CrossRef][ISI][Medline]
8. French AJ, Weller CV. Interstitial myocarditis following the clinical and experimental use of sulfonamide drugs. Am J Pathol 1942;18:109-121. [ISI]
9. Fenoglio JJ Jr, McAllister HA Jr, Mullick FG. Drug related myocarditis. I. Hypersensitivity myocarditis. Hum Pathol 1981;12:900-907. [CrossRef][ISI][Medline]
10. Burke AP, Saenger J, Mullick F, Virmani R. Hypersensitivity myocarditis. Arch Pathol Lab Med 1991;115:764-769. [ISI][Medline]
11. Salzman MB, Valderrama E, Sood SK. Carbamazepine and fatal eosinophilic myocarditis. N Engl J Med 1997;336:878-879. [Free Full Text]
12. Ansari A, Maron BJ, Berntson DG. Drug-induced toxic myocarditis. Tex Heart Inst J 2003;30:76-79. [ISI][Medline]
13. Killian JG, Kerr K, Lawrence C, Celermajer DS. Myocarditis and cardiomyopathy associated with clozapine. Lancet 1999;354:1841-1845. [CrossRef][ISI][Medline]
14. Langsjoen PH, Stinson JC. Acute fatal allergic myocarditis: report of a case. Dis Chest 1965;48:440-441. [CrossRef][ISI][Medline]
15. Barrett DA II, Dalldorf FG, Barnwell WH II, Hudson RP. Allergic giant cell myocarditis complicating tuberculosis chemotherapy. Arch Pathol 1971;91:201-205. [ISI][Medline]
16. Herzog CA, Snover DC, Staley NA. Acute necrotising eosinophilic myocarditis. Br Heart J 1984;52:343-348. [Free Full Text]
17. Taliercio CP, Olney BA, Lie JT. Myocarditis related to drug hypersensitivity. Mayo Clin Proc 1985;60:463-468. [ISI][Medline]
18. deMello DE, Liapis H, Jureidini S, Nouri S, Kephart GM, Gleich GJ. Cardiac localization of eosinophil-granule major basic protein in acute necrotizing myocarditis. N Engl J Med 1990;323:1542-1545. [ISI][Medline]
19. Getz MA, Subramanian R, Logemann T, Ballantyne F. Acute necrotizing eosinophilic myocarditis as a manifestation of severe hypersensitivity myocarditis: antemortem diagnosis and successful treatment. Ann Intern Med 1991;115:201-202. [Free Full Text]
20. Galiuto L, Enriquez-Sarano M, Reeder GS, et al. Eosinophilic myocarditis manifesting as myocardial infarction: early diagnosis and successful treatment. Mayo Clin Proc 1997;72:603-610. [Abstract]
21. Kazama R, Okura Y, Hoyano M, et al. Therapeutic role of pericardiocentesis for acute necrotizing eosinophilic myocarditis with cardiac tamponade. Mayo Clin Proc 2003;78:901-907. [Free Full Text]
22. Kim CH, Vlietstra RE, Edwards WD, Reeder GS, Gleich GJ. Steroid-responsive eosinophilic myocarditis: diagnosis by endomyocardial biopsy. Am J Cardiol 1984;53:1472-1473. [CrossRef][ISI][Medline]
23. Cooper LT, Zehr KJ. Biventricular assist device placement and immunosuppression as therapy for necrotizing eosinophilic myocarditis. Nat Clin Pract Cardiovasc Med 2005;2:544-548. [CrossRef][ISI][Medline]
24. Aggarwal A, Bergin P, Jessup P, Kaye D. Hypersensitivity myocarditis presenting as cardiogenic shock. J Heart Lung Transplant 2001;20:1241-1244. [CrossRef][ISI][Medline]
25. Lee C-W, Mitchell RN, Horan RF, Castells MC. Cardiogenic shock and peripheral eosinophilia in a young woman. Ann Allergy Asthma Immunol 2005;95:229-233. [ISI][Medline]
26. Rosenstein ED, Zucker MJ, Kramer N. Giant cell myocarditis: most fatal of autoimmune diseases. Semin Arthritis Rheum 2000;30:1-16. [ISI][Medline]
27. Burke JS, Medline NM, Katz A. Giant cell myocarditis and myositis: associated with thymoma and myasthenia gravis. Arch Pathol 1969;88:359-366. [ISI][Medline]
28. Namba T, Brunner NG, Grob D. Idiopathic giant cell polymyositis: report of a case and review of the syndrome. Arch Neurol 1974;31:27-30. [Medline]
29. Litovsky SH, Burke AP, Virmani R. Giant cell myocarditis: an entity distinct from sarcoidosis characterized by multiphasic myocyte destruction by cytotoxic T cells and histiocytic giant cells. Mod Pathol 1996;9:1126-1134. [ISI][Medline]
30. Ishikawa H, Kaneko H, Watanabe H, Takagi A, Ming ZW. Giant cell myocarditis in association with drug-induced skin eruption. Acta Pathol Jpn 1987;37:639-644. [Medline]
31. Adachi Y, Yasumizu R, Hashimoto F, et al. An autopsy case of giant cell myocarditis probably due to a non-steroidal anti-inflammatory drug. Pathol Int 2001;51:113-117. [CrossRef][ISI][Medline]
32. Daniels PR, Berry GJ, Tazelaar HD, Cooper LT. Giant cell myocarditis as a manifestation of drug hypersensitivity. Cardiovasc Pathol 2000;9:287-291. [CrossRef][ISI][Medline]
33. Gravanis MB, Hertzler GL, Franch RH, et al. Hypersensitivity myocarditis in heart transplant candidates. J Heart Lung Transplant 1991;10:688-697. [ISI][Medline]

Source : http://content.nejm.org/cgi/content/full/357/21/2167