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Welcome to the European Society of Cardiology. Our mission: to reduce the burden of cardiovascular disease in Europe
 
01 Oct 2008

Fulminant lymphocytic myocarditis versus giant cell myocarditis 

The clinical case of the month: October 2008

Topics: Myocardial Disease
Authors: Gotsman, I. and Keren A.

Case Presentation

A 76 year old female was admitted in 2007 due to excertional dyspnea, chest discomfort, fatigue and a short lasting fever a few days prior to her admission. Two weeks earlier she experienced right facial weakness followed by ptosis of the right eyelid which gradually improved. Her medical history included an anterior myocardial infarction in 1993 that was treated with streptokinase with reperfusion. Due to angina she underwent a coronary angiogram in 2000 that demonstrated a long diffuse atheroma in the mid left anterior descending artery with near complete occlusion and good collateral flow. She was treated conservatively.

Echocardiography at the time demonstrated preserved left ventricular function with apical hypokinesis. She was physically active with good functional capacity until the present admission. She also suffered from well controlled hypertension, mild diabetes mellitus, hyperlipidemia and chronic atrial fibrillation. Her medications included atenonol 50mg BD, aspirin 100mg BD, hydrochlorozide 25mg, simvastatin 80 and coumadin. On physical examination she was afebrile, had mild dyspnea, a blood pressure of 111/75 mmHg and an irregular pulse of 102/min. Oxygen saturation on room air was 92%. She had distant irregular heart sounds, her lungs were clear to auscultation and the extremities were without edema.

Electrocardiogram revealed atrial fibrillation, right bundle branch block, Q waves & ST-T changes in the inferior leads. The electrocardiogram was not significantly different from a previous electrocardiogram. Troponin-T was elevated to 5.5 ng/ml (normal < 0.1) and CPK was 346 U/L (normal < 170). LDH reached 1525 U/L (normal < 420), CRP was elevated to 13.5 mg% (normal < 1) and the white blood count was normal.




What would be the diagnosis and appropriate management of this patient at this time?

As the patient had chest discomfort, dyspnea, ECG changes and elevated cardiac enzymes, the diagnosis included an acute coronary syndrome however myocarditis was also a possible diagnosis. The patient was planned for echocardiography and a diagnostic coronary angiogram. Prior to these examinations, on the day of admission, she suddenly developed cardiogenic shock with severe dyspnea, reduced blood pressure and congestion on X-ray. Troponin-T rose to 7.5 ng/ml.

She was treated aggressively with an intra-aortic balloon pump (IABP), inotropes and intravenous diuretics that stabilized her condition. Echocardiography revealed severe biventricular failure, diffusely decreased left ventricular contraction with significant mitral regurgitation and no pulmonary hypertension. Mitral regurgitation was not due to a flail leaflet or a ruptured chord. Left and right coronary catheterization revealed no significant change in coronary anatomy from previous examination with a severe stenosis in the mid left anterior descending artery which filled retrogradely from the right coronary. There was no pulmonary hypertension and no pulmonary artery branch cutoffs. Cardiac index was measured at 1.5 l/min/m2. Endomyocardial biopsy was performed (Figure 1.). The biopsy revealed severe diffuse myocyte necrosis, a predominantly lymphocytic infiltrate with sparse giant cells.

What would be the appropriate management of this patient at this time?

Figure 1.
Histological specimen (H&E staining) from the right ventricle demonstrating severe, diffuse necrotizing lymphocytic myocarditis. [1A]Areas of diffuse myocardial necrosis with large infiltrates of lymphocytes (black arrow). [1B] Severe myocardial necrosis and a nucleated giant cell can be seen (black arrow).

Areas of diffuse myocardial necrosis

Severe myocardial necrosis

Answers:

As the biopsy suggested severe necrotizing myocarditis, the differential diagnosis included fulminant lymphocytic myocarditis versus giant cell myocarditis. She was treated with an angiotensin converting enzyme inhibitor, beta blockers and furosemide. Immunosuppressive therapy was considered due to possible giant cell myocarditis. This treatment was not given due to rapid clinical improvement with supportive therapy and the endomyocardial biopsy suggestive of a pathological diagnosis of lymphocytic and not giant cell myocarditis.

The patient was weaned from the IABP after 3 days. Repeat echocardiogram 5 days later demonstrated significant improvement in left ventricular function. A comprehensive immunological and infectious work-up was negative. The final pathological diagnosis was severe, diffuse necrotizing lymphocytic myocarditis. Follow-up 16 months after the event revealed the patient to be free of heart failure with preserved left ventricular function on echocardiography.

Discussion:

The patient presented with an acute event that at presentation it was not clear if the patient was suffering from an acute coronary event (ACS) or from acute myocarditis. As the patient was an elderly woman with significant risk factors and a history of ischemic heart disease, the diagnosis of ACS versus myocarditis can be difficult. While myocarditis occurs more frequently in young people, myocarditis is not uncommon in the elderly.

The diagnosis is often dismissed or overlooked in the elderly due to coexistent coronary disease. Inflammatory indices as well as echocardiography can be very helpful in making the diagnosis; however they are not always conclusive. Even performing a coronary angiogram may not give a definite diagnosis, particularly in a patient with previous complex coronary disease as was in the case presented.

The need for myocardial biopsy to prove or disprove a diagnosis

Fortunately, in the present case we could compare the coronary anatomy to a previous angiogram and conclude that there was no change suggesting that the coronary lesion was most probably not the culprit of the present insult. Indeed, the diagnosis of myocarditis versus ischemia frequently necessitates a myocardial biopsy to prove or disprove the diagnosis. Unexplained, new-onset heart failure of less than two weeks’ duration associated with hemodynamic compromise is a class I indication for endomyocardial biopsy according to recent AHA/ACC guidelines 1 and was indicated in the present case.

Even a myocardial biopsy may be inconclusive due to the patchy nature of myocarditis and the considerable sampling error associated with establishing the diagnosis of myocarditis 2. The use of MRI T2 imaging and early gadolinium contrast enhancement as well as late enhancement that detects small areas of myocardial necrosis associated with active myocarditis may increase the diagnostic yield of endomyocardial biopsy by guiding the site of tissue sampling 3,4. Indeed, recent data suggests a promising role for magnetic resonance imaging (MRI) in discriminating myocarditis from myocardial infarction 5. MRI can demonstrate evidence of acute active inflammation by increase T2 imaging signal while infarction or fibrosis can be detected by late gadolinium enhancement.

Cardiogenic shock

Our patient rapidly deteriorated into cardiogenic shock. This is a classical presentation of fulminant myocarditis: patients are critically ill, with acute severe LV dysfunction and hemodynamic instability. However, these patients have a good long-term outcome 6. This differs significantly from patients with acute or subacute myocarditis that are initially less ill but have a progressive course that leads to death or the need for cardiac transplantation. As the prognosis of patients with fulminant myocarditis is excellent if they survive the initial insult, these patients should be treated aggressively in the intensive care unit 6. They should receive full hemodynamic support including vasopressors and mechanical support by an intra-aortic balloon pump or a left ventricular assist device. Standard heart failure therapy should also be started as soon as possible. However, immunosuppressive therapy is not indicated in patients with fulminant myocarditis as this has not shown to improve prognosis in the Myocarditis Treatment Trial 7.

Giant-cell myocarditis?

Another acute myocardial inflammatory disease that can resemble fulminant myocarditis is giant-cell myocarditis. Although rare, this disease is rapidly progressive and leads to progressive congestive heart failure, frequently associated with refractory ventricular arrhythmia and conduction disturbances. Patients with this disease frequently have other autoimmune diseases. The diagnosis is based on identifying the typical nucleated giant cells on myocardial biopsy in addition to lymphocytes, histiocytes and eosinophiles.

This disease in contrast to fulminant myocarditis carries a poor prognosis. Treatment should include steroids with immunosuppressive therapy including cyclosporine and/or azathioprine that significantly improves prognosis 8. Transplantation can also be an alternative despite the possibility of recurrence in the transplanted heart.

In our patient, the fact that only a few giant cells were found without eosinophiles in the biopsy as well as the rapid clinical improvement with supportive therapy led us to the conclusion that we are dealing with a case of fulminant lymphocytic myocarditis and not giant cell myocarditis. Her immediate and long term clinical course also supported this diagnosis.

While acute heart failure in myocarditis can be a life threatening event and the diagnosis can be elusive, timely action with rapid diagnostic tests including a myocardial biopsy and rapid aggressive treatment can help improve the outcome of patients with this disease.

The authors wish to thank Dr Leslie T. Cooper and Dr William D. Edwards from Rochester, MN, USA for their advice in the management of this patient.


Notes to editor
By Israel Gotsman M.D. and Andre Keren M.D., from the Heart Failure and Heart Muscle Disease Center, Heart Institute, Hadassah University Hospital, Jerusalem, Israel.
References References
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2. Chow LH, Radio SJ, Sears TD, McManus BM. Insensitivity of right ventricular endomyocardial biopsy in the diagnosis of myocarditis. J Am Coll Cardiol.
1989;14:915-20.
3. Mahrholdt H, Goedecke C, Wagner A, Meinhardt G, Athanasiadis A, Vogelsberg H, Fritz P, Klingel K, Kandolf R, Sechtem U. Cardiovascular magnetic resonance assessment of human myocarditis: a comparison to histology and molecular pathology. Circulation. 2004;109:1250-8.
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5. Assomull RG, Lyne JC, Keenan N, Gulati A, Bunce NH, Davies SW, Pennell DJ, Prasad SK. The role of cardiovascular magnetic resonance in patients presenting with chest pain, raised troponin, and unobstructed coronary arteries. Eur Heart J. 2007;28:1242-9.
6. McCarthy RE, 3rd, Boehmer JP, Hruban RH, Hutchins GM, Kasper EK, Hare JM, Baughman KL. Long-term outcome of fulminant myocarditis as compared with acute (nonfulminant) myocarditis. N Engl J Med. 2000;342:690-5.
7. Mason JW, O'Connell JB, Herskowitz A, Rose NR, McManus BM, Billingham ME, Moon TE. A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators. N Engl J Med. 1995;333:269-75.
8. Cooper LT, Jr., Berry GJ, Shabetai R. Idiopathic giant-cell myocarditis--natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators. N Engl J Med. 1997;336:1860-6.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.