In recent years, there have been many advances in the diagnosis and treatment of arrhythmias in children. This paper focuses on some of these advances, and gives an overview of relevant studies. Special attention is paid to technological advances that have created the possibility of using devices like an implantable loop recorder or an implantable cardioverter-defibrillator (ICD) in even small children. Further attention has been given to the use of molecular genetic analysis, of importance in identifying pre-symptomatic patients with congenital long QT syndrome (LQTS), and in identifying pre-symptomatic patients in families with sudden unexplained death at young age.
Implantable Loop Recorders
In patients with recurrent syncope, conventional investigations sometimes are inconclusive. Long-term recording of the cardiac rhythm in these patients may reveal a correlation between symptoms and rhythm. The implantable loop recorder (Reveal, Medtronic, Minneapolis, MN) has been available since 1997; it can record the cardiac rhythm during syncope and has a battery lifespan of at least 14 months. Although many studies have reported its role in adults, at present its role in paediatric patients is less well defined. However, symptoms of syncope and palpitations are common in childhood. Usually the underlying cause is benign and already clear after taking history, physical examination, and non-invasive diagnostics like an electrocardiogram and possibly 24-hour Holter monitoring. If symptoms are very infrequent and life-threatening causes cannot be excluded, or when invasive therapy as an ICD implantation is considered, it is of paramount importance to establish a symptom-rhythm correlation (see Figure 1). Previous studies show that use of an implantable loop recorder in children gives an excellent correlation with symptoms.1-4 It will give an underlying cause in a significant number of patients, while in patients with no underlying arrhythmia it will prevent further invasive diagnostics.
Long QT Syndrome
LQTS is the most prevalent cardiac channelopathy. Other cardiac channelopathies include Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), and idiopathic ventricular fibrillation. These heritable arrhythmia syndromes stem from defective ion channels in the heart.
Congenital LQTS is characterised by QT prolongation on the electrocardiogram causing ventricular arrhythmias leading to syncope and sudden death.5 Congenital LQTS can be divided in two clinical entities: Romano-Ward syndrome is inherited as an autosomal dominant trait, while Jervell and Lange-Nielsen syndrome (JLNS) is inherited as an autosomal recessive disorder. Romano-Ward syndrome is caused by heterozygous mutation in one of the eight different genes that have currently been identified (KCNQ1 (LQT1 syndrome), KCNH2 (LQT2 syndrome), SCN5A (LQT3 syndrome), KCNE1, KCNE2, ANK2, KCNJ2, and Cav1.2). JLNS is caused by homozygous or compound heterozygous mutations in KCNQ1 or KCNE1 and is associated with congenital sensorineural deafness, while Romano-Ward syndrome is not associated with additional malformations.
The clinical syndrome of LQTS is highly variable. Many patients are pre-symptomatic mutation carriers, who can even have a normal QT interval on the electrocardiogram. On the other hand, sudden cardiac death may be the first manifestation of LQTS. There is a significant difference in age at first cardiac event between the various mutations. The mean age at first cardiac event in an LQT1 patient is nine years, in an LQT2 patient 12 years and in an LQT3 patient the mean age at first cardiac event is 16 years. Warning symptoms are palpitations, seizures or syncope, especially during exercise (see Figure 2 and Figure 3). When the diagnosis of LQTS is established, β-blocker therapy should be instituted. This therapy reduces the risk of sudden cardiac death and a nearly normal life expectancy may be expected. However, some patients remain symptomatic despite adequate β-blocker therapy, and in these patients ICD implantation should be considered. Left cardiac sympathetic denervation may be effective in a selected subgroup of patients. Special attention should be given to patients with the LQT3 mutation. β-blockers are less effective in this subgroup, and symptoms usually occur at rest. Therefore, a low heart rate should be prevented. Pacemaker insertion, in combination with sodium channel blockade, may improve the prognosis considerably.
JLNS is a very severe variant of LQTS. Despite β-blocker therapy about half of the patients remain or become symptomatic and 27% of the patients suffer cardiac arrest or sudden death. Early ICD implantation must be considered in these patients.6
When LQTS is diagnosed in a patient, relatives should be tested by electrocardiography and exercise stress testing. This screening is very important, since pre-symptomatic mutation carriers may show sudden cardiac death as first symptom, which can be prevented by β-blocker therapy.
In all patients with clinical LQTS molecular genetic screening should be performed. In about 70% of cases the causative gene mutation can be found. This may help further screening of family members, who may be pre-symptomatic and have a normal ECG while still being at risk of life-threatening arrhythmias, especially when using medication that may further prolong the QT interval.
All patients with LQTS should receive a list of medications that should be avoided, and should be given advice about sports activities that may or may not be undertaken. Symptomatic LQTS patients should be advised against competitive sports, and should be strongly warned against swimming without adequate supervision, given the risk of drowning.7
Implantable Cardioverter-Defibrillator
In adults, implantation of an ICD has become the treatment of choice for patients who survive sudden cardiac death. Large prospective trials has also shown the benefit of an ICD as primary prevention for certain patient categories. These studies, however, have showed its effectiveness in adults who had myocardial infarction (MI) and reduced ejection fraction.8 The main indications for ICD implantation in the paediatric population include prevention of life-threatening arrhythmias caused by primary electrical diseases,9 cardiomyopathy and previous corrections for congenital heart disease (CHD). Studies in children show that even in the youngest patients ICD implantation is technically possible, and most patients benefit from the implantation (see Figure 4). Overall survival during medium-term follow-up is good.10-11 However, there are some potential complications in children that need careful consideration. In very young children the endovascular approach is less useful, and alternative procedures have been developed such as the placement of epicardial patches and abdominal placement of the generator.12 The high incidence of inappropriate shocks in children may limit the use of ICDs. It may be difficult to differentiate between sinus or supraventricular tachycardia and ventricular tachycardia.
This may be prevented by increasing the detection time and rate, and by use of dual chamber systems with a supraventricular discrimination algorithm. The psychological impact of an ICD must not be underestimated. Eicken et al. reported in their study about half of the patients showing signs of generalised depression and/or anxiety. They suggested psychological surveillance in all young patients with an ICD.10
Sudden Cardiac Death
Sudden cardiac death is a major cause of death among adults, and is then mainly related to ischaemic heart disease. The incidence of sudden cardiac death at young age is remarkably lower, about one to eight per 100,000 patient years. The underlying causes may be diverse, including cardiomyopathies (hypertrophic or dilated) and primary electrical diseases (LQTS, Brugada syndrome, CPVT, primary ventricular fibrillation (VF)). About half of the causes of sudden death can be recognised by autopsy, such as in the case of hypertrophic cardiomyopathy, myocarditis, or congenital or achieved coronary artery abnormalities. Patients with negative autopsy findings remain a challenging group. These patients may have had potentially inherited diseases that, if recognised earlier, might have been suitable for preventative strategies.13-15 A careful family history with special attention to sudden cardiac death and recurrent syncope at a young age is the first step. All first degree family members should be investigated by physical examination, electrocardiogram, exercise stress testing and echocardiography. When a clinical diagnosis is made further molecular genetic analysis may identify the underlying mutation. This protocol will identify about 40% of causes of sudden cardiac death in patients with normal findings at autopsy.15 Many of these families may then be treated by β-blockers and ICD implantation and can receive adequate information about possible lifestyle restrictions.
Conclusions
In young patients with recurrent syncope and in whom a definitive diagnosis cannot be established by conventional diagnostics the implantation of an implantable loop recorder is now feasible, and often gives the diagnosis. In patients with LQTS the prophylactic use of β-blockers has led to a major reduction in the risk of sudden death. By molecular genetic screening, more pre-symptomatic gene carriers can be unmasked. If an ICD is necessary in young patients this is possible in even the youngest patients. However, its psychological impact must not be underestimated. In families with sudden unexplained death at young age screening of the family members may lead to a diagnosis in about 40% of cases, and therefore makes pre-symptomatic prevention of sudden death possible in many people.