This is a 12-year-old male presenting to the pediatric cardiology office with a chief complaint of syncope. One week prior to this clinic visit he was playing beach volleyball with his friends on a rather hot afternoon. After about 20 minutes of playing in the game he was found collapsed on the middle of the volleyball court. When his friends approached him, he was pale, unconscious and he had jerky movements resembling a convulsion. The rhythmic jerky movements involved his entire body and lasted about 10 seconds. Soon after the movements stopped, he slowly regained consciousness and open his eyes. At first, he was disoriented, but stood up and felt better within 2 minutes. He complained of some lightheadedness, being nervous, but did not have any other symptoms until the ambulance arrived. The ambulance took him to a general emergency department, where his vital signs were all within normal limits except for tachycardia (HR 110 bpm). An electrocardiogram (ECG) was obtained, which reportedly showed sinus tachycardia (HR of 105), but no ST segment changes. A comprehensive metabolic panel showed mild dehydration with a BUN of 19. Cardiac enzymes were obtained: troponin I and CPK-MB were within normal limits. The patient did not complain of dizziness, palpitations, shortness of breath or chest pain, so he was discharged with counseling about appropriate hydration and referred to cardiology for follow-up.
On further questioning in the cardiology office, he admits to having had 2 similar episodes within the last 2 years, both of which occurred right after he stopped playing basketball. He also remembers having a few episodes of dizziness lasting for a couple of seconds, but he did not lose consciousness. He denies having palpitations, chest pain, shortness of breath or any other symptoms associated with these episodes. He does not feel any prodrome prior to the loss of consciousness. The next thing he remembers is laying on the ground, waking up surrounded by his friends.
His family history is unremarkable: no sudden death, no frequent fainting, no congenital heart defects, no deafness. He has no other medical problems, and he is very active and athletic.
Vital signs in the cardiology office: pulse 80, respiratory rate 20, BP 110/65, oxygen saturation 99%, height 155 cm (77%ile), weight 45 kg (70%ile).
He is alert and active in no distress. Neuro: Oriented, normal tone, normal reflexes, no focal deficits. Head: normocephalic, without signs of trauma or dysmorphic features. Chest: symmetric, no deformity. Heart: regular rate, regular rhythm, normal precordial activity, no thrill, normal S1, physiologically split S2, no systolic or diastolic murmur, no additional heart sounds, no gallop or rub.
Clinical course: A repeat ECG was obtained at the cardiology office that revealed the diagnosis. It showed normal sinus rhythm at a rate of 82 bpm with regular rate and rhythm, normal leftward axis, normal PR at 160 msec, normal QRS at 82 msec, an abnormally broad based QT segment measuring 459 msec with a QTc of 536 msec. He was started on a beta-blocker in order to prevent further arrhythmias. He was cautioned not to engage in more than minimal physical exercise and avoid swimming. Genetic testing was obtained that revealed a mutation in the KCNQ1 gene consistent with Long QT Syndrome type 1. Within 3 months of the evaluation he had another episode of syncope at his school during PE. An automated external defibrillator (AED) was applied to his chest while he was unconscious and it delivered a shock that probably saved his life. The AED recorded a fatal arrhythmia: torsade de pointes. He recovered from the sudden cardiac arrest without any residual neurologic deficit. Shortly after this episode he received an automated implantable cardioverter defibrillator (AICD) and was restricted from exercise.
SYNCOPE
Syncope is defined as a sudden loss of consciousness with loss of stature. It is due to the sudden decrease of oxygenated blood perfusion to the brain. If the cause of cerebral hypoperfusion resolves within 1-2 minutes, the consciousness returns. It is not uncommon to observe convulsions during the episode of syncope, which is attributed to the sudden lack of oxygen and glucose to neurons resulting in disorganized neuronal activity. If the cause of cerebral hypoperfusion persists and the individual does not get prompt medical help with cardiopulmonary resuscitation (CPR), permanent damage may occur.
Syncope is a relatively common symptom, affecting mostly teenagers and young adults. Annually, more than 1 million pediatric ED visits have been recorded due to syncope in the United States. The etiology is variable, ranging from transient dehydration, through orthostatic hypotension to potentially fatal cardiac arrhythmias. Luckily, most of the patients presenting with syncope have a benign etiology, however a small percentage of patients may harbor a potentially fatal disease: cardiac channelopathy or cardiomyopathy. Separating the wheat from the chaff requires a systematic and methodical review of the circumstances of the syncope, the past medical history and the family history, a focused physical examination, and further medical evaluation that should always include an electrocardiogram (ECG)!
The etiology of syncope can be divided into the following categories:
1) Neurologic
2) Metabolic
3) Autonomic
4) Cardiac
Neurologic causes resulting in loss of consciousness includes seizures, migraines and hysteria induced hyperventilation. An important element in identifying a neurologic etiology of the loss of consciousness is the recognition of preceding neurologic symptoms, such as headache, visual changes and seizure activity. Sometimes it might be difficult to sort out what came first: the convulsion or the syncope. Generalized seizures usually present with complete loss of consciousness. It is easy to recognize generalized tonic-clonic convulsion, but sometimes seizures may only have a tonic component or present with loss of muscle tone, and in those cases it is more difficult to recognize the seizure. Focal seizures may not result in loss of consciousness and therefore they do not result in syncope or collapse. Typically, following a seizure, there is a period of disorientation, altered mental status that may last from 5 to 20 minutes. It is unusual to have a complete recovery of consciousness and mental status within a minute after the convulsion stops and the individual awakens. This can be also helpful in determining whether a seizure is the underlying cause of the loss of consciousness or a syncope occurred first with following convulsions.
Metabolic problems, such as severe hypoglycemia and electrolyte disorders may result in syncope and loss of consciousness as well. Since the onset of most metabolic problems is gradual, there are usually significant symptoms minutes to hours prior to the loss of consciousness. These symptoms may include lightheadedness, dizziness, nausea, emesis, blurry vision, headache or abdominal pain. If the symptoms are not recognized, the metabolic problem can progress to a point where basic cellular functions are altered and the integrity of complex neuronal activity and arousal is compromised. Usually, it is not difficult to differentiate between such a gradual onset metabolic condition and a sudden onset cardiac related syncope.
Autonomic etiology of syncope is by far the most common. It is important to understand the physiology of the autonomic dysfunctions that can lead to loss of consciousness are the following entities:
a) vasovagal syncope
b) situational syncope
c) orthostatic hypotension induced syncope
d) exercise related syncope
Even in the cardiology office, the most common final diagnosis with the chief complaint of syncope is vasovagal syncope. Vasovagal syncope, or common faint, is also called neurocardiogenic syncope. The loss of consciousness occurs in susceptible rather young individuals triggered by prolonged standing. Standing, especially in warm weather, allows blood pooling in the venous system of the lower extremities. This results in relative depletion in the circulating intravascular volume. To a certain extent, everybody can compensate with increasing the arterial blood pressure through vasoconstriction and increasing the cardiac output by increased heart rate. However, after a certain period, the autonomic nervous system cannot further compensate for lack of circulating blood and rebound bradycardia occurs. The bradycardia suddenly drops the cardiac output resulting in loss of consciousness. The onset of loss of consciousness is somewhat gradual: the person usually feels lightheaded first followed by blurry vision, decreased visual fields, dizziness and within seconds complete black-out. It is not uncommon that due to the loss of cerebral perfusion, convulsions can occur for a few seconds or even up to a minute. Once the person is in the supine position, the pooled blood from the lower extremities returns to the heart, and the increased cardiac preload increases the cardiac output. The improved cerebral perfusion results in normal neuronal activity, and the person regains the consciousness. Usually, loss of consciousness due to a vasovagal syncope does not last more than a couple of minutes. Once awake, there isn't any residual confusion or altered mental status; the person regains complete consciousness. Feeling of fatigue and lightheadedness may persist and a second syncope may occur if the person gets up to standing position right after the first episode.
Vasovagal syncope can also occur when a sudden increase in vagal tone (triggered by activities such as straining, combing one's hair, sudden cold water) decreases the cardiac output and blood pressure. This entity blends into the so-called situational syncope, when a certain situation results in increased vagal tone and loss of consciousness. The most famous of all is the fainting teenage girl at the sight of blood. This is not a heart disease, rather it is an exaggerated autonomic response to external stimuli. The mechanism is very simple; an external stimulus triggers increased vagal tone that drops the heart rate and the blood pressure. In susceptible individuals this can be so severe that in response to certain stimuli cardiac asystole occurs for up to 30-60 seconds. Once the vagal response dissipates, heart rate and blood pressure return to normal and the individual regains consciousness. Again, convulsions may occur during cerebral hypoperfusion.
Sometimes, severe orthostatic hypotension may result in syncope. Usually this occurs when getting up from sitting or supine position. In the sitting and supine positions, blood flows easily to the heart and the venous vascular tone is low. When changing to standing position, the low venous vascular tone allows blood pooling in the lower extremities and it takes a few seconds to develop reflex tachycardia to compensate for the acute loss of cardiac preload. In the interim, individuals can get lightheaded, dizzy, can develop blurry vision and even faint.
Exercise related syncope occurs within 1-5 minutes from the termination of exercise. During exercise the heart rate increases, the systolic blood pressure increases and the diastolic blood pressure remains stable. At the end of exercise, in certain individuals, the sudden drop of blood pressure and heart rate causes transient decrease in cerebral blood flow and it may lead to syncope. This response is exaggerated if the person is dehydrated. Dehydration causes decreased intravascular volume and predisposes to hypotension. Further perspiration during exercise worsens the dehydration and sometimes in the midst of exercise, most often right after the exercise, this condition may lead to cerebral hypoperfusion inducing loss of consciousness and collapse.
Cardiac causes of syncope are not as common, but are the most dangerous. That is why this chapter is discussed under the cardiology section. We can further divide the cardiac etiology to the following problems:
a) plumbing/pump problems: myocardial dysfunction and obstructive lesions
b) electrical problems: arrhythmias and bradycardia
Plumbing/pump problems including myocardial dysfunction and obstructive lesions will always present with preceding symptoms, such as shortness of breath, exercise intolerance, respiratory distress and fatigue. Syncope is usually not the first or the only presenting sign. These problems include dilated cardiomyopathy with decreased myocardial function, hypertrophic obstructive cardiomyopathy, aortic or pulmonic stenosis and pulmonary hypertension. All of these conditions can be diagnosed with echocardiography. It is extremely rare in the pediatric population to encounter coronary vasculopathy induced myocardial infarction and acute myocardial dysfunction with syncope. The conditions listed usually have a gradual onset and worsening symptoms. The symptoms of fatigue may not be recognized at first, but upon focussed questioning, these patients always have symptoms besides syncope.
Electrical problems however, usually occur in previously healthy individuals and may present with no previous symptoms or suspicious signs. Electrical disorders of the heart (officially termed as Hereditary Arrhythmia Syndromes) can cause potentially fatal arrhythmias or sudden onset of heart block with bradycardia. The hereditary arrhythmia syndromes can be divided to cardiomyopathies and channelopathies. Patients with hypertrophic, dilated or arrhythmogenic cardiomyopathies have abnormal cardiomyocytes that form a disarrayed myocardium. The myocardial pathology predisposes to the development of ventricular arrhythmias due to subendocardial ischemia or intrinsic arrhythmogenicity. Channelopathies on the other hand are a group of disorders with ion channel mutations including long QT syndrome, short QT syndrome and Brugada syndrome. The mutations affect K (potassium), Na (sodium) or Ca (calcium) channels leading to abnormal action potentials in the cardiomyocytes. Mutations in the gene of the K-channel can cause long QT syndrome or short QT syndrome with prolonged or shortened repolarization, respectively. The length of the QT interval may prolong or shorten depending on loss of function or gain of function of the K-channels governing cardiac repolarization. Na and Ca channel mutations may lead to abnormal depolarization or repolarization and can be found in Brugada syndrome (loss of function) or in long QT syndrome (gain of function). These hereditary arrhythmia syndromes and their pathognomic and diagnostic ECG findings are summarized in the table below.
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SUDDEN CARDIAC ARREST
Sudden cardiac arrest (SCA) in the pediatric population is under-recognized. Based on recent publications, 10-25% of sudden infant death syndrome (SIDS) and at least 25-50% of sudden unexpected death syndrome (SUDS) is caused by channelopathies and cardiomyopathies, the hereditary arrhythmia syndromes (HAS). The pathology behind SCA in children and young adults can be divided into structural defects and electrical problems:
1) structural problems:
. . . . . a) hypertrophic cardiomyopathy (HCM)
. . . . . b) coronary artery anomalies
. . . . . c) Marfan syndrome and aortic rupture
. . . . . d) dilated cardiomyopathy (DCM)
. . . . . e) arrhythmogenic right ventricular cardiomyopathy (ARVC)
. . . . . f) postoperative congenital heart disease
2) electrical problems
. . . . . a) long QT syndrome (LQTS)
. . . . . b) Brugada syndrome (BrS)
. . . . . c) catecholaminergic polymorphic ventricular tachycardia (CPVT)
. . . . . d) Wolff-Parkinson-White syndrome
. . . . . e) short QT syndrome (SQTS)
. . . . . f) complete heart block
. . . . . g) commotion cordis
Although HCM, DCM and ARVC are listed among structural disorders, the mechanism of sudden cardiac arrest in those entities is clearly electrical. Most of the HAS (including LQTS, SQTS, BrS, CPVT, ARVC, HCM, DCM) are inherited with an autosomal dominant pattern, however there are few with autosomal recessive inheritance, such as Jervell & Lange-Nielsen syndrome (LQTS).
Pathophysiology of arrhythmias and sudden cardiac arrest
Patients with channelopathies have abnormal depolarization or repolarization in the cardiac action potential. Arrhythmias however, present only under specific conditions or particular circumstances. In LQTS, BrS and SQTS, exercise, sleep or sudden stimuli may cause arrhythmias. Due to defective ion channels, fast heart rate or a sudden change in heart rate (long-short interval) causes certain areas in the heart to depolarize and repolarize at a different time. With different depolarization and repolarization synchrony, certain areas may be relatively refractory when the next action potential comes along. Relative refractoriness causes slow propagation of the action potential through the affected area and could potentially allow the action potential to turn around and hit already repolarized adjacent areas setting up a reentry circuit within the ventricular wall. This reentry circuit maintained by abnormal de- or repolarization ignites ventricular arrhythmias, such as ventricular tachycardia and torsade de pointes. Frequently, arrhythmias occur during exercise, swimming, with sudden stimuli or at sleep in patients with channelopathies.
Cardiomyopathies on the other hand cause ventricular arrhythmias with a different mechanism. Exercise or circumstances with increased oxygen demand and/or elevated systemic blood pressure, result in higher heart rates and shortening of diastole, during which the diastolic coronary blood flow decreases, while the oxygen demand of the myocardium increases. In a thick, hypertrophic or dilated ventricle, the subendocardial myocardium receives even less blood flow and develops ischemia due to increased wall stress or lack of appropriate blood supply. Ischemia causes abnormal cardiomyocyte function and triggers unorganized electrical activity leading to ventricular fibrillation.
Ventricular tachycardia and ventricular fibrillation results in severely decreased cardiac output and decreased brain and heart perfusion can lead to syncope and sudden cardiac arrest.
Signs and symptoms
Most of the patients with Hereditary Arrhythmia Syndromes (HAS) are fine until they are not. This means that they are asymptomatic and have a completely normal physical exam until the arrhythmias manifest. Patients with HAS may present with syncope in about 30% of the cases. The syncope is usually sudden without any prodrome as opposed to vasovagal syncope. Loss of consciousness is caused by the sudden drop of cardiac output and decreased brain perfusion due to fast or disorganized ventricular activity (ventricular tachycardia or ventricular fibrillation). In 10% of patients, the arrhythmias may present as convulsions and can be easily mistaken for seizure disorder. In fact, many patients with channelopathies and arrhythmias presenting as convulsions are treated for a potential seizure disorder. The convulsions are caused by insufficient brain perfusion and oxygen delivery secondary to the drop of cardiac output during a ventricular arrhythmia. Every patient with a seizure and completely normal EEG and brain MRI should have an ECG in order to discover or rule out HAS. Some patients may present with brief palpitations, sometimes during or after exercise. It is plausible that brief ventricular arrhythmias do not cause a sustained drop of cardiac output and therefore do not result in loss of consciousness. Unfortunately, about 10% of patients with HAS do not have any symptoms and the first presenting sign is sudden cardiac arrest. These individuals can be saved only if appropriate CPR is initiated within a minute of the incident followed by applying an AED that terminates the ventricular arrhythmia.
Again, the most important parts of the evaluation of syncope are taking a meticulously detailed history of the events and a critical examination of the ECG.
Treatment and Management
There is no curative treatment for channelopathies and cardiomyopathies besides heart transplantation. Once recognized, the management of hereditary arrhythmia syndromes focuses on primary prevention of arrhythmias and sudden cardiac arrest, and secondary prevention of sudden cardiac death. Although, there are accepted guidelines about medical management and indication for AICD implantation, the actual therapy is individualized and depends on the specific gene mutation.
An abnormal genotype, alas the presence of a genetic mutation encoding an ion channel consistent with LQTS or Brugada syndrome, does not mean that the individual will necessarily develop arrhythmias. Depending on the location of the defective amino acid in the structure of the ion channel, the function of the ion channel can be seriously affected, mildly affected or not affected at all. There are known disease causing mutations and some that are not associated with an abnormal phenotype, therefore do not pose a risk of arrhythmias and sudden cardiac arrest. Moreover, even with known disease causing mutations, the penetrance can be variable and the amount of abnormal ion channels in the heart can vary not only from patient to patient, but also during the lifetime of a single individual. Obviously, if a child or young adult presents with symptoms such as syncope, or has an abnormal ECG, the phenotype is present. Medical treatment should be tailored to the type of HAS, the severity of the phenotype and the underlying genotype of every single patient.
Management of patients with HAS includes exercise restriction, medication, and implantation of an automated defibrillator if necessary. In general, to prevent arrhythmias in LQTS, beta-blockers are the first line of therapy. Children are given propranolol, while teenagers and adults preferably treated with nadolol or metoprolol (avoid atenolol). Beta-blockers decrease the heart rate and prevent or decrease the possibility of reentry circuit formation. CPVT and cardiomyopathies may also be "treated" with beta-blockers; however certain patients with LQTS and BrS due to a Na or Ca channel mutation do not benefit much from beta-blockade, and may be better served by Na-channel blockers. Unfortunately, primary prevention is frequently unsuccessful and despite appropriate exercise restriction and medical therapy, arrhythmias and sudden cardiac arrest may occur. In patients with aborted sudden cardiac arrest and a documented ventricular arrhythmia or HAS, implantable automated cardioverter defibrillator placement is indicated.
The prognosis of patients depends on the type of syndrome and the phenotype. There are children with known LQTS, who have no symptoms whatsoever and do not require any medication in their lifetime, while others may need medical therapy and IACD placement for secondary prevention. However, without the specific diagnosis and risk assessment, children with HAS may be at risk of sudden cardiac death, so appropriate evaluation including meticulous history taking and ECG is paramount.
Questions
1. Which of the following is the most common cause of syncope?
. . . . . a) Situational
. . . . . b) Vasovagal
. . . . . c) Cardiac
. . . . . d) Neurologic
2. What mutations may result in long QT syndrome?
. . . . . a) Na-channel
. . . . . b) K-channel
. . . . . c) Ca-channel
. . . . . d) All of the above
3. Which condition is a hereditary arrhythmia syndrome?
. . . . . a) Critical aortic stenosis
. . . . . b) Marfan syndrome
. . . . . c) Brugada syndrome
. . . . . d) Noonan syndrome
4. What is an appropriate strategy to prevent arrhythmias in patients with long QT syndrome?
. . . . . a) Propranolol
. . . . . b) Digoxin
. . . . . c) Atenolol
. . . . . d) IACD
5. What is the mechanism of sudden cardiac death in Brugada syndrome?
. . . . . a) Cardiac ischemia
. . . . . b) LV outflow obstruction
. . . . . c) Ventricular reentry tachycardia
. . . . . d) Atrial fibrillation with rapid ventricular response
References
Moya A, Sutton R, Ammirati F, et al. Guidelines for the diagnosis and management of syncope (version 2009). Europace. 2009; 30:2631-2671.
Morita H, Wu J, Zipes DP. The QT syndromes: long and short. Lancet. 2008; 372:750-763.
Campbell R, Berger S, Ackerman MJ, et al. Pediatric sudden cardiac arrest. Pediatrics. 2012; 129:1094-1102.
Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies. Europace. 2011; 13:1077-1109.
Arnestad M, Crotti L, Rognum T, et al. Prevalence of long-QT syndrome gene variants in sudden infant death syndrome. Circulation. 2007; 115:361-367.
Reybrouck T, Ector H. Chapter 12 - Syncope and assessment of autonomic function in children. In: Allen HD, Driscoll DJ, Shaddy RE, Feltes TF (eds). Heart Disease in Infants, Children, and Adolescents, 7th edition. 2008, Baltimore: Lippincott Williams and Wilkins, pp. 269-274.
Answers to questions
1. b
2. d
3. c
4. a
5. c