**5.3 Echocardiography**

50 Myocarditis

Chest radiography and electrocardiography (ECG) can be used as first line diagnostic modality (Figure 3). Most common ECG changes are sinus tachycardia, axis deviation, ventricular hypertrophy and ST-T wave changes (Freedman et al., 2007). Moreover, evidence from previous studies suggests that the presence of northwest axis deviation, new left bundle branch block and abnormal QRS complexes is correlated with higher rates of transplantation or death (Magnani et al., 2006, Morgera et al.,1992, Nakashima et al., 1998, Greenwood et al. 1976). A recent adult study have shown that QRS prolongation is an independent predictor for transplantation or death in patients with suspected myocarditis (Ukena et al., 2011). In the majority of cases of myocarditis (up to 90%), abnormal chest radiography was documented (Durani et al., 2009, Freedman et al., 2007). Most common chest radiography finding is cardiomegaly, followed by pulmonary edema and pulmonary

Fig. 4. M-mode echocardiography (a) and chest x-ray (b) of an adolescent girl with

hospital with dyspnea and tachycardia. She had a history of preceding viral upper

presumed viral myocarditis. M-mode echocardiography demonstrating systolic dysfunction with flattened interventricular septum. In chest radiography, there was prominent diffuse vascular congestion that is compatible with pulmonary edema. 13 year old girl admitted our

respiratory infection. The patient intubated and connected to mechanical ventilation on day one of emergency room admission. She died within 72 hours after initial presentation.

General markers for inflammation such as erythrocyte sedimentation rate and C-reactive protein in serum are commonly elevated. However, their usage in diagnosis of myocarditis is limited. Freedman et al. demonstrated that the most sensitive marker for myocarditis was an increased aspartate transaminase (AST). AST elevation was found in 85% of probable and definite cases of myocarditis (Freedman et al., 2007). On the other hand, C-reactive protein and erythrocyte sedimentation rate have been elevated in cases of myocarditis with a range of 27 to 56%. Cardiac troponin t (cTnT) has also been investigated as a diagnostic marker for acute myocarditis since 1990's. cTnT, a contractile protein unique to cardiac muscle, is vastly concentrated in the myocytes and will be released into the blood within hours after heart muscle injury. Following myocardial cell necrosis an increased concentration of cTnT is noticable in blood for more than a week. Cardiac troponin T measurements are especially useful in clinical settings in which traditional enzyme determinations fail to diagnose myocardial cell damage effectively. Likewise, cTnT is not reliably corresponded to increases

**5.1 Electrocardiography and chest radiography** 

infiltrate (Figure 4).

**5.2 Laboratory finding** 

Echocardiographic features of myocarditis are nonspecific. Patterns of echocardiography in myocarditis could mimic hypertrophic, dilated or right ventricular cardiomyopathy and as well as ischemic heart disease (Checcia&Kulik, 2006). Echocardiography can be used for assessing wall thickness, cardiac chamber size together with systolic and diastolic functions. Right ventricular dysfunction is relatively unusual. However, right ventricular dysfunction was found to be predictor of adverse outcome in patients with active myocarditis (Mendes et al., 1994). Left ventricular diastolic dysfunction with a restrictive pattern is also observed in most cases of myocarditis. Left ventricular wall thickening was found to be highest on days 1-3 after onset of acute myocarditis. It has also been noted that left ventricular thickening was more marked in the fulminant myocarditis (Felker et al., 2006). On the contrary to adult patients, echocardiographic findings of pediatric patients revealed that relatively thicker posterior wall was correlated with better prognosis and recovery (Carvalho et al., 1996). Segmental wall motion abnormalities are relatively frequent, but global hypokinesis is prevalent. Pericardial effusion commonly occurs. The presence of thrombi in ventricle has also been documented in up to 25% of cases (Daly et al., 1983).

Fig. 5. Cardiac magnetic resonance imaging of acute myocarditis in a adolescent. In four chamber and short axis view, subepicardial late enhancement are noted. Text and image courtesy of Alper Yuksel, Yigit Goktay.

### **5.4 Magnetic resonance imaging**

Current practice has focused on the use of cardiac magnetic resonance imaging (CMR) for the diagnosis of acute myocarditis (Gutberlet et al., 2008, Friedrich et al., 1998). CMR with a

**5.5 Biopsy** 

**6. Treatment** 

Myocarditis in Childhood: An Update on Etiology, Diagnosis and Management 53

Despite its limitations, EMB is the gold standard for diagnosis of myocarditis. Together with simultaneous PCR and immunohistology, rapid detection of the viral genome is possible (Checcia&Kulik, 2006). The Dallas criteria have regulated the definition of myocarditis (Aretz et al., 1987). Active myocarditis is considered if light microscopy shows infiltrating lymphocytes and cytolysis. One of the potential advantage of this procedure it may aid physician in determining the management of myocarditis. Children with viral myocarditis may benefit from therapy with immune suppression while patients with cardiomyopathy may not (Liu et al., 2001). Several issues have to be considered before making a decision about biopsy. As stated earlier, some complications such as pneumothorax, dysrhythmia, perforation and death, may occur during the procedure, and it can be hazardous for particularly pediatric patients (Pophal et al., 1999). Limited sensitivity of EMB that is related with sampling error should also be evaluated (Hauck et al., 1989). Substantial controversy exist with respect to diagnostic criteria for examining tissue specimens. Poor interobserver variability may limit the utility of Dallas criteria (Shanes et al., 1987). A scientific statement from the American Heart Association, The American College of Cardiology and European Society of Cardiology published in 2007, has evaluated the role of EMB in myocarditis (Cooper et al., 2007). Various clinical scenarios have been described. Of these only two have received class I recommendation for EMB (Table). In a retrospective review analyzing the morbidity and mortality of EMB in children, highest risk was found in children with suspected myocarditis on inotropic support (Pophal et al., 1999). Authors also found that risk of biopsy in small children (< 10 kg) or sick infants was extreme. Compared with established risk of EMB in adults, there is an increased risk in children. Thus, careful risk-

In spite of the significant progress in understanding the mechanisms of myocarditis pathogenesis in last two decades, advances in treatment strategies are still limited and the supportive care is the principal therapy. Most patients with acute myocarditis presenting with dilated cardiomyopathy respond favorably to standard anticongestive therapy including afterload reduction, diuretics, angiotensin converting enzyme inhibitors and the introduction of β blockers such as carvedilol or metoprolol succinate once the acute phase is controlled. Various experimental studies with β adrenoreceptor inhibitors or agonists showed different effects in acute myocarditis. Treatment with propranolol in mice infected with encephalomyocarditis virus (EMCV) reduced the severity of myocarditis and mortality (Wang et al., 2005). On the other hand, carvedilol, non-selective β blocker, improved the survival and decreased the virus replication of mice infected with EMCV through the enhancement of IL-12 and IFN-γ production, whereas metoprolol had no effect on this murine model (Nishio et al., 2003). Despite the lack of extensive studies in pediatric patients, administration of carvedilol has been found to be associated with improvement of left ventricle function and clinical symptoms and normalization of antioxidant enzyme activity (Bajcetic et al., 2008). Similar to effects of β blockers, ACE inhibitors and angiotensin receptor blockers have been documented to lessen viral myocardial injury in murine models (Yamamoto et al., 2003). It is also proposed that early introduction of beta-blockers and ACE inhibitors might prevent the remodelling that advances to dilated cardiomyopathy (Ellis&DiSalvo, 2007). Phosphodiesterase inhibitors such as milrinone, if well tolerated, can

benefit analysis should be therefore undertaken for each patient.

unique potential for tissue characterization, particularly with the utilization of T1 and T2 weighted images, can assess 3 markers of tissue injury, which is, hyperemia and capillary leakage, necrosis and fibrosis and intracellular and interstitial edema (Friedrich et al., 2009). CMR visualizes the entire myocardium, recognizing borders of inflammation from later modeling. Thus, it can be used to monitor lesions and be used to show the execution of endomyocardial biopsy, as well as it may be useful in the quantification of the magnitude of damage (Danti et al., 2009, Mahroldt et al., 2004). Goitein et al. demonstrated that cardiac MRI have a larger impact than echocardiography in verifying the existence of myocarditis and evaluating the extent of disease (Goitein et al., 2009). It has been shown that echocardiography is useful in revealing wall motion abnormalities, whereas cardiac MRI could actually identify the often subtle patchy myocardial inflammation (Friedrich et al., 1998). Gadolinium is used as a contrast agent due to ability to penetrate cells whose membranes ruptured and allows contrast agent to diffuse into the cells (Weinmann et al., 1984). Myocardial blood flow and edema, that is likely to be increased in tissues which are inflamed, could augment signal enhancement in MRI. But, cardiac MRI features can be missed on the first pass perfusion (Skouri et al., 2006). Delayed enhancement MRI permits visualization of necrotic and fibrotic myocardium (Friedrich et al., 2009). The observations obtained from the studies using contrast media-enhanced cardiac MRI indicate that pattern of myocarditic lesions occur predominantly in the lateral free wall and get localized to the subepicardial or intramyocardial regions (Mahroldt et al., 2004, Friedrich et al., 1998). The finding of lateral free wall involvement (subepicardial region) partially explain why some young patients with acute myocarditis can present with only ST elevation on ECG (Figure 5). Postmortem studies also showed that lateral wall was the preferred location in myocarditis (Theleman et al., 2001, Shirani et al., 1993). Subendocardial region involvement pattern which is typical for myocardial infarction was never seen in patients with acute myocarditis (Mahroldt et al., 2004). Mahroldt et al. also demonstrated that in the right ventricle half of septum, that is common location of EMB, had relatively low density of inflammatory cells. Apart from lateral free wall pattern, Marhold et al showed that HHV6 myocarditis had pattern that was located in midwall area of the interventricular septum. Pericardial effusion has also been reported in 32 to 57% of cases with myocarditis (Friedrich et al., 2009). Its presence, although not specific for myocarditis, is a supportive evidence for active inflammation.

Recently, International Consensus Group on Cardiovascular Magnetic Resonance suggested the diagnostic criteria, known as ''Lake Louis Consensus Criteria'' (Friedrich et al., 2009). Cardiac MRI should be made in the setting of clinically suspected myocarditis according to these criteria. It was also stated that maximum diagnostic accuracy can be accomplished with the presence of any two or more of the following criteria: Regional or global myocarditis signal increases in T2 weighted images, increased global myocardial early gadolinium enhancement ratio between myocardium and skeletal muscle (T1 weighted images) or presence of at least one focal lesion with nonischemic regional distribution (late gadolinium enhancement).

In a retrospective study published in 2009, researchers found that myocarditis in children is characterized mainly by subepicardial and transmural enhancement. Global hypokinesia, left ventricular dilatation, ejection fraction less than 30% and transmural myocardial involvement were discovered to be associated with poor outcome (Vashist et al., 2009).

### **5.5 Biopsy**

52 Myocarditis

unique potential for tissue characterization, particularly with the utilization of T1 and T2 weighted images, can assess 3 markers of tissue injury, which is, hyperemia and capillary leakage, necrosis and fibrosis and intracellular and interstitial edema (Friedrich et al., 2009). CMR visualizes the entire myocardium, recognizing borders of inflammation from later modeling. Thus, it can be used to monitor lesions and be used to show the execution of endomyocardial biopsy, as well as it may be useful in the quantification of the magnitude of damage (Danti et al., 2009, Mahroldt et al., 2004). Goitein et al. demonstrated that cardiac MRI have a larger impact than echocardiography in verifying the existence of myocarditis and evaluating the extent of disease (Goitein et al., 2009). It has been shown that echocardiography is useful in revealing wall motion abnormalities, whereas cardiac MRI could actually identify the often subtle patchy myocardial inflammation (Friedrich et al., 1998). Gadolinium is used as a contrast agent due to ability to penetrate cells whose membranes ruptured and allows contrast agent to diffuse into the cells (Weinmann et al., 1984). Myocardial blood flow and edema, that is likely to be increased in tissues which are inflamed, could augment signal enhancement in MRI. But, cardiac MRI features can be missed on the first pass perfusion (Skouri et al., 2006). Delayed enhancement MRI permits visualization of necrotic and fibrotic myocardium (Friedrich et al., 2009). The observations obtained from the studies using contrast media-enhanced cardiac MRI indicate that pattern of myocarditic lesions occur predominantly in the lateral free wall and get localized to the subepicardial or intramyocardial regions (Mahroldt et al., 2004, Friedrich et al., 1998). The finding of lateral free wall involvement (subepicardial region) partially explain why some young patients with acute myocarditis can present with only ST elevation on ECG (Figure 5). Postmortem studies also showed that lateral wall was the preferred location in myocarditis (Theleman et al., 2001, Shirani et al., 1993). Subendocardial region involvement pattern which is typical for myocardial infarction was never seen in patients with acute myocarditis (Mahroldt et al., 2004). Mahroldt et al. also demonstrated that in the right ventricle half of septum, that is common location of EMB, had relatively low density of inflammatory cells. Apart from lateral free wall pattern, Marhold et al showed that HHV6 myocarditis had pattern that was located in midwall area of the interventricular septum. Pericardial effusion has also been reported in 32 to 57% of cases with myocarditis (Friedrich et al., 2009). Its presence, although not specific for myocarditis, is a supportive evidence for

Recently, International Consensus Group on Cardiovascular Magnetic Resonance suggested the diagnostic criteria, known as ''Lake Louis Consensus Criteria'' (Friedrich et al., 2009). Cardiac MRI should be made in the setting of clinically suspected myocarditis according to these criteria. It was also stated that maximum diagnostic accuracy can be accomplished with the presence of any two or more of the following criteria: Regional or global myocarditis signal increases in T2 weighted images, increased global myocardial early gadolinium enhancement ratio between myocardium and skeletal muscle (T1 weighted images) or presence of at least one focal lesion with nonischemic regional distribution (late

In a retrospective study published in 2009, researchers found that myocarditis in children is characterized mainly by subepicardial and transmural enhancement. Global hypokinesia, left ventricular dilatation, ejection fraction less than 30% and transmural myocardial involvement were discovered to be associated with poor outcome (Vashist et al., 2009).

active inflammation.

gadolinium enhancement).

Despite its limitations, EMB is the gold standard for diagnosis of myocarditis. Together with simultaneous PCR and immunohistology, rapid detection of the viral genome is possible (Checcia&Kulik, 2006). The Dallas criteria have regulated the definition of myocarditis (Aretz et al., 1987). Active myocarditis is considered if light microscopy shows infiltrating lymphocytes and cytolysis. One of the potential advantage of this procedure it may aid physician in determining the management of myocarditis. Children with viral myocarditis may benefit from therapy with immune suppression while patients with cardiomyopathy may not (Liu et al., 2001). Several issues have to be considered before making a decision about biopsy. As stated earlier, some complications such as pneumothorax, dysrhythmia, perforation and death, may occur during the procedure, and it can be hazardous for particularly pediatric patients (Pophal et al., 1999). Limited sensitivity of EMB that is related with sampling error should also be evaluated (Hauck et al., 1989). Substantial controversy exist with respect to diagnostic criteria for examining tissue specimens. Poor interobserver variability may limit the utility of Dallas criteria (Shanes et al., 1987). A scientific statement from the American Heart Association, The American College of Cardiology and European Society of Cardiology published in 2007, has evaluated the role of EMB in myocarditis (Cooper et al., 2007). Various clinical scenarios have been described. Of these only two have received class I recommendation for EMB (Table). In a retrospective review analyzing the morbidity and mortality of EMB in children, highest risk was found in children with suspected myocarditis on inotropic support (Pophal et al., 1999). Authors also found that risk of biopsy in small children (< 10 kg) or sick infants was extreme. Compared with established risk of EMB in adults, there is an increased risk in children. Thus, careful riskbenefit analysis should be therefore undertaken for each patient.
