**5. Diagnosis**

48 Myocarditis

0502 and DQB1\* 0504 present protection from IDC (Liu et al., 2005). However, associations of MHC class II alleles with dilated cardiomyopathy are possibly affected by ethnicity, sex, age and geographical variations. Besides the MHC haplotype, non- MHC genes should be considered (Neu et al., 1987). Two non-MHC loci on murine chromosomes 1 and 6, referred as Eam1 and Eam2, respectively, might influence autoimmune myocarditis (Guler et al., 2005). These loci intersect with loci implicated in other autoimmune diseases, such as lupus and diabetes, might give a clue that various autoimmune disease could be controlled by related genetic mechanisms. Initial antiviral response by the host has been recognized to be mediated at least in part by Toll-like receptors. TLR3 was found to play a significant role in the host innate immune response to infection with several cardiotropic viruses. Recent data suggests that variations in TLR3 alter the innate immune response and might change host

As stated previously, clinical picture of myocarditis is extremely variable, ranging from asymptomatic ECG abnormalities to heart failure (Dec et al., 1985, Bowles et al., 2003). The term ''*Acute* fulminant myocarditis'' is used for cases with severe congestive heart failure or cardiogenic shock (Amabile et al., 2006). Age of child influences clinical presentation of myocarditis (Dec et al., 1985). Viral prodrome of flu-like illness, respiratory symptoms or gastroenteritis may precede symptoms of heart failure. Neonates and infants present with poor feeding, irritability or listlessness, diaphoresis, apnea and episodic pallor. Usual symptoms of congestive heart failure, as well as mild cyanosis and pallor are observed on physical examination. It should be emphasized that neonates and affected younger infants may have intrauterine myocarditis with chronic course (Bowles et al., 2003). For very young infants acquiring myocarditis in the peripartal period, the prognosis is very poor, with more than 90% of children dying. Previous studies have implicated the myocarditis as the cause of sudden death (Friedman et al., 1998, Bowles et al., 2003). In the retrospective study of Krous et al., they evaluated the infants who died of sudden death infant syndrome in a safe sleep environment, accidental suffocation or myocarditis were assessed, and they have noticed the manifestation of scattered inflammatory cells and necrotic myocyte were noticed (Krous et al., 2009). From this observation, they suggested that few scattered inflammation and necrotic myocyte were normal finding in the developing heart exposed to new environmental pathogens. However, degree of cardiac infiltration was found to be greater in infants who died of myocarditis. In German study published in 2004, researchers found that viral myocardial affection is the cause of death in cases with SIDS (Dettmeyer et al., 2004). Besides, it was proposed by authors that PVB19 seems to play a more significant role than

Recent history of viral disease 10 to 14 days preceding presentation typically occurs in older children and adolescents (Friedman et al., 1998). Nonspecific gastrointestinal and respiratory complaints are more common than chest pain (Vashist&Singh, 2009). Jugular venous distension and pulmonary rales may be seen, and the resting tachycardia may be obvious, unlike in neonates. Since symptoms of myocarditis vary considerably in children, diagnosis can be challenging. Durani and colleagues, documented that most patients present with complaints of shortness of breath having tachypnea at presentation (Durani et al., 2009). Vomiting (48%) and poor feeding (40%) are also commonly seen in myocarditis. The authors also observed that the diagnosis of myocarditis was missed on the first presentation

susceptibility to increased cardiovascular pathology (Gorbea et al., 2010).

**4. Clinical features** 

presumed so far.

Although the misdiagnosis of the myocarditis is common, several diagnostic methods can aid physicians in making diagnosis of the myocarditis.

Fig. 3. 12 lead ECG in children with myocarditis. Negative T wave in DI, aVL, ST-T changes were noted in precordial leads.

Myocarditis in Childhood: An Update on Etiology, Diagnosis and Management 51

in blood of cardiac enzymes or myoglobin in all cases of Wolff-Parkinson-White syndrome undergoing radiofrequency ablation. Cardiac troponin I, subunit of thin filament of contractile element of the myocardium, has high specificity (89%) and low sensitivity (34%) in adult patients with acute myocarditis, whereas cTnT has been documented to have a specificity of 83% and sensitivity of 71% in children. Moreover, higher levels of cTnT have been demonstrated to be a prognostic marker for poor outcome in adults presenting with acute myocarditis. Elevated levels of interleukin-10 (IL-10) and TNF appears to be predictor of fulminant myocarditis. Besides this, increase of serum Fas and Fas ligand levels, as well as immunohistological signs of inflammation (CD3 and/or CD68) on initial presentation are

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

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

associated with fatal outcome in patients with acute myocarditis.

**5.3 Echocardiography** 

courtesy of Alper Yuksel, Yigit Goktay.

**5.4 Magnetic resonance imaging** 

### **5.1 Electrocardiography and chest radiography**

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 infiltrate (Figure 4).

Fig. 4. M-mode echocardiography (a) and chest x-ray (b) of an adolescent girl with 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 hospital with dyspnea and tachycardia. She had a history of preceding viral upper 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.

#### **5.2 Laboratory finding**

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 in blood of cardiac enzymes or myoglobin in all cases of Wolff-Parkinson-White syndrome undergoing radiofrequency ablation. Cardiac troponin I, subunit of thin filament of contractile element of the myocardium, has high specificity (89%) and low sensitivity (34%) in adult patients with acute myocarditis, whereas cTnT has been documented to have a specificity of 83% and sensitivity of 71% in children. Moreover, higher levels of cTnT have been demonstrated to be a prognostic marker for poor outcome in adults presenting with acute myocarditis. Elevated levels of interleukin-10 (IL-10) and TNF appears to be predictor of fulminant myocarditis. Besides this, increase of serum Fas and Fas ligand levels, as well as immunohistological signs of inflammation (CD3 and/or CD68) on initial presentation are associated with fatal outcome in patients with acute myocarditis.
