In children and young adults, sudden cardiac death (SCD) occurs in approximately 1-2 per 100,000 population.1,2 While the overwhelming majority of occurrences of SCD occur in the adult population and are due to ischemic heart disease, very few cases in a pediatric population are. Pediatric SCD is a relatively uncommon occurrence whose underlying etiology often remains elusive. A long list of relatively rare and varied conditions accounts for SCD in previously well children.2-5 The implications for recurrences and risk in other family members are far-reaching, and more poignant than in the case of adult ischemic heart disease.The consequences for the family are devastating and the lack of an explanation leaves the family searching and uncertain of how to proceed.
Diagnostic Approach
A detailed history is potentially life-saving when seeing the young survivor of resuscitated SCD or a family with a history of SCD.When possible, booking a longer appointment is advisable. The family often has a lot to discuss; extended family may attend; and there are usually a lot of unresolved psychosocial issues that arise. Since the number of 'near-misses' for each condition causing SCD is unknown, each is an opportunity to prevent SCD in the future. There are often warning clues available in the history. It is imperative to get a detailed history of the circumstances preceding the event. Although it may seem difficult to discuss the event with the family, most families are eager to do whatever it takes to uncover an etiology for SCD. Collapse or syncope during exertion is common to a variety of causes of SCD and not usually a distinguishing feature. Death during sleep is seen in some forms of long QT syndrome and Brugada syndrome. The patient's exercise tolerance cannot be taken at face value; a detailed understanding of what sort of exertional effort was required to 'keep up' is needed. Similarly, the family history must be explored in depth for cases of 'fainting', 'heart attack' and 'seizures'. One must know whether one is dealing with a positive family history and a heritable condition, or a sporadic case.
The physical examination is directed at uncovering signs of cardiovascular disease. The general appearance and growth parameters will provide clues about whether the SCD is due to an undiagnosed chronic condition, such as cardiomyopathy or underlying heart disease. The precordium may be active or the apex displaced in cases of cardiac enlargement.
Cardiac auscultation is usually unremarkable in cases presenting with SCD later in childhood; the corollary is that findings of valvular heart disease or cyanotic heart disease should be detected in infancy.The association of mitral valve prolapse with SCD is a poorly understood one and may not withstand the scrutiny of an unselected population.6 A subtle gallop rhythm may be the only auscultatory finding in cardiomyopathy. Hypertrophic cardiomyopathy often has an ejection murmur associated with it.
Investigations
An electrocardiogram (ECG) is the minimum investigation required in evaluating the patient at risk of SCD. Many primary electrical diseases can only be diagnosed from a surface ECG. Pre-excitation, indicative of the Wolff-Parkinson-White syndrome, manifests as a short PR interval and corresponding widened QRS. P waves not conducted to the ventricle is indicative of heart block.This congenital or acquired entity is associated with sudden death in the both the asymptomatic and the post-operative patient. Manual measurement of the QT interval is the expected standard; a mathematical adjustment is performed to standardize the numerical value. The morphology of the repolarization is indicative of the Brugada syndrome and usually abnormal in long QT syndrome.
Echocardiography is adequate for most structural heart disease. Echocardiography will be diagnostic in cases of cardiomyopathy when performed in facilities familiar with pediatric studies. Coronary artery origins can typically be visualized in the young patient.
Even in cases of SCD not associated with exertion, an exercise test is capable of providing diagnostic clues. Ventricular ectopy that increases during peak exertion, particularly that not suppressed at higher stages of the protocol, occurs in long QT syndrome, catecholaminergic polymorphic ventricular tachycardia and several forms of cardiomyopathy. Decreased exercise tolerance may be uncovered in cases of cardiomyopathy. The repolarization in long QT syndrome patients may be more abnormal in the recovery phase of exercise than during the exertion.7
It is difficult to define an area of cardiac imaging that has seen more growth than magnetic resonance imaging (MRI).In investigating SCD, MRI has an established role in arrhythmogenic right ventricular cardiomyopathy (ARVC).The applications will continue to increase with the excellent resolution, lack of radiation, and relative non-invasive nature of the study.8
There is an evolving role for drug challenges and genetic testing, directed by the clues from the initial survey. Preliminary work suggests that a systematic approach including adrenaline and procainamide challenges increases the yield in cases of unexplained SCD.9 Review of relevant autopsy reports should be undertaken as a minimum. Since not all pathologists are trained in the nuances of the pediatric cardiac autopsy, review by a pediatric pathologist at a later juncture may be helpful.
Primary Electrical Diseases
Wolff-Parkinson-White Syndrome
Accessory pathways conducting from the atrium to ventricle provide the substrate for re-entrant arrhythmias. While atrioventricular (AV) reciprocating tachycardia is typically well tolerated in young, otherwise healthy individuals, patients with Wolff-Parkinson-White syndrome are at risk of developing atrial fibrillation (AF). The accessory pathway allows bypass of the AV node, and rapid conduction of the atrial impulses to the ventricle may result in ventricular fibrillation.This is uncommon, occurring in 1/1,000 patients with Wolff-Parkinson-White syndrome.10,11
Long QT Syndrome
Perhaps no other condition in cardiology has traversed the divide between basic science and clinical medicine as effectively as long QT syndrome (LQTS) has. LQTS is a group of heritable disorders due to a host of mutations in the genes that encode the ion channels controlling cardiac action potential. There are three main sub-types—two potassium channelopathies predisposing to SCD during emotion or exercise; the remaining sodium channelopathy is associated with death unrelated to exertion.The mechanism of death is a polymorphic ventricular tachycardia known as torsade de pointes, due to after-depolarizations. Despite tremendous advances in the understanding of the genetics and pathophysiology of LQTS, risk stratification continues to be a major clinical challenge.
Short QT Syndrome
As it was becoming apparent that the lower limit of a normal QT interval was a moving target, there appeared isolated reports of patients with abnormally short repolarization with arrhythmias. Families with SCD and ventricular fibrillation with short QT syndrome have been described.The prevalence and pathophysiology of this entity are still being elucidated, as very few patients with this entity have been described.12,13
Catecholaminergic Polymorphic Ventricular Tachycardia
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is likely an under-recognized cause of SCD. With a normal physical examination, echocardiogram and resting ECG, a high index of suspicion is required to diagnose CPVT. This heritable abnormality of calcium handling presents with exertional arrhythmia, syncope and SCD. The appearance of multi-focal ventricular ectopy on exercise testing is characteristic, although an adrenaline challenge may also helpful. The mutations are most commonly in the ryanodine receptor, resulting in abnormal after-depolarizations, although the mechanisms underlying the arrhythmia and SCD are still being sought.14
Brugada Syndrome
This channelopathy is not often seen in a pediatric population, although the original report did describe three children in a series of eight subjects.15 The characteristic ECG demonstrates ST elevation in the right precordial leads.This is a common cause of SCD in young asian males and events frequently occur at rest or during sleep. Brugada syndrome bears similarities to LQTS, not restricted to the shared sodium channel mutations in some patients. Sodium channel blockers, such as procainamide, may help unmask latent Brugada syndrome.
Structural Heart Disease
SCD remains the most important cause of death in palliated congenital heart disease (CHD). Tetralogy of Fallot, a complex ventricular septal defect associated with pulmonary outflow obstruction, is the most common lesion associated with late SCD in the current era. As more complex lesions are managed more routinely, the list of those associated with SCD increases. For example, the infant with single ventricle physiology, even after an initial operation, has a high risk of demise.16,17 Unrecognized CHD continues to account for a few cases of SCD each year at most pediatric centers.18
Coronary Anomalies
Coronary artery anomalies usually occur in the setting of CHD.When encountered as an isolated anomaly, it is usually an incidental finding. The origin of the coronary artery from the opposite sinus of Valsalva is frequently encountered in autopsy series examining SCD.19 Many of the patients with this anomaly are asymptomatic and experience SCD in association with exercise. The management of asymptomatic patients with this anomaly who do not have ostial compromise is controversial.
Cardiomyopathy
Cardiomyopathy is a non-specific term and there are several types of heart muscle abnormality associated with SCD. Perhaps the most well-known of these is hypertrophic cardiomyopathy.This is the most common heritable substrate for SCD in young individuals, occurring in as many as one in 500 individuals.20 Hypertrophic cardiomyopathy results from a variety of mutations in at least 11 genes determining sarcomeric structure and function.21 Another form of cardiomyopathy is arrhythmogenic right ventricular cardiomyopathy (ARVC).While LQTS has illuminated the bench to bedside model, ARVC has troubled clinicians and investigators alike. ARVC is a progressive cardiomyopathy involving fibro-fatty replacement of portions of the right ventricle. This results in re-entrant ventricular tachyarrhythmias originating from the right ventricle, with a left bundle branch pattern. Heart failure may develop in the later stages of the disease, as the structure of the heart gradually changes. Despite a hereditary component, there is an incomplete understanding of the genetics, variable penetrance, and the progressive pathology.22
Left ventricular non-compaction is an abnormality of endomyocardial development in which there are prominent left ventricular trabeculations and intertrabecular recesses.23 Originally thought to be quite rare, this cardiomyopathy has been increasingly reported to be associated with arrhythmias and SCD.24,25 It is likely however that this entity represents a number of conditions with similar echocardiographic appearance with varying underlying causes and clinical course.
Conclusion
Sudden cardiac death in the young individual is a tragedy for the family and the community left behind. The cause is rarely obvious to the novice observer and the temptation to quickly attach a label must be resisted until a thorough review is undertaken. A thorough history and focused investigation may uncover causes where none was initially apparent. The implications for surviving family members cannot be overstated, both from a medical risk and a psychosocial perspective. Familiarity with the some of the more common categories of conditions will allow the physician to direct the evaluation.