Author + information
- Received November 24, 2013
- Revision received February 15, 2014
- Accepted February 26, 2014
- Published online June 3, 2014.
- Giulio Conte, MD∗∗ (, )
- Wendy Dewals, MD†,
- Juan Sieira, MD∗,
- Carlo de Asmundis, MD∗,
- Giuseppe Ciconte, MD∗,
- Gian-Battista Chierchia, MD∗,
- Giacomo Di Giovanni, MD∗,
- Giannis Baltogiannis, MD∗,
- Yukio Saitoh, MD∗,
- Moises Levinstein, MD∗,
- Mark La Meir, MD‡,
- Francis Wellens, MD‡,
- Gudrun Pappaert, RN∗ and
- Pedro Brugada, MD∗
- ∗Heart Rhythm Management Centre, UZ Brussel-VUB, Brussels, Belgium
- †Pediatric Department, UZ Brussel-VUB, Brussels, Belgium
- ‡Cardiac Surgery Department, UZ Brussel-VUB, Brussels, Belgium
- ↵∗Reprint requests and correspondence:
Dr. Giulio Conte, Heart Rhythm Management Centre, Cardiovascular Division, UZ Brussel-VUB, Laarbeeklaan 101, 1090 Brussels, Belgium.
Objectives The goal of this study was to investigate the clinical features, management, and long-term follow-up of children with drug-induced Brugada syndrome (BS).
Background Patients with BS <12 years of age with a spontaneous type I electrocardiogram have a higher risk of arrhythmic events. Data on drug-induced BS in patients <12 years of age are lacking.
Methods Among 505 patients with ajmaline-induced BS, subjects ≤12 years of age at the time of diagnosis were considered as children and eligible for this study.
Results Forty children (60% male; age 8 ± 2.8 years) were included. Twenty-four children (60%) had a family history of sudden death. Two (5%) had a previous episode of aborted sudden death, and 8 (20%) had syncope. Children experienced more frequent episodes of sinus node dysfunction (SND) compared with older subjects (7.5% vs. 1.5%; p = 0.04) and had a comparable incidence of atrial tachyarrhythmias. Children more frequently experienced episodes of ajmaline-induced sustained ventricular arrhythmias (VAs) compared with older patients (10.0% vs. 1.3%; p = 0.005). Twelve children (30%) received an implantable cardioverter-defibrillator (ICD). After a mean follow-up time of 83 ± 51 months, none of the children died suddenly. Spontaneous sustained VAs were documented in 1 child (2%). Among children with ICD, 1 (8%) experienced an appropriate shock, 4 (33%) had inappropriate ICD shocks, and 4 (33%) experienced device-related complications.
Conclusions Drug-induced BS is associated with atrial arrhythmias and SND. Children are at higher risk of ajmaline-induced VAs. The rate of device-related complications, leading to lead replacement or inappropriate shocks, is considerable and even higher than with appropriate interventions. Based on these findings, the optimal management of BS in childhood should remain individualized, taking into consideration the patient's clinical history and family's wishes.
Brugada syndrome (BS) is an inheritable syndrome characterized by coved-type ST-segment elevation in the right precordial leads (V1 to V3) and increased risk of sudden death (SD) in the absence of structural heart disease (1). Pharmacological challenge with ajmaline, a potent sodium channel blocker with a short half-life, is the recommended test to unmask the diagnostic Brugada electrocardiogram (ECG) pattern in patients with suspected BS and nondiagnostic ECG (2). Although in the initial description of a series of 8 patients with BS, 3 individuals were children (including the first and the second patients ever diagnosed with the syndrome), subsequent studies revealed that prevalence of BS in the pediatric population is extremely low (0.0098%) compared with the adult population (0.14% to 0.7%) (3,4). Moreover, the mean age of patients presenting with either symptomatic or asymptomatic BS is reportedly in the fourth or fifth decade (5). Clinical aspects and prognosis of either spontaneous or drug-induced BS have been previously described in individuals <16 years of age, and, as in adults, a higher risk of arrhythmic events has been found in symptomatic patients and in those displaying a spontaneous type I ECG (6). However, specific data on the clinical characteristics and prognosis of drug-induced BS in patients <12 years of age are lacking. In addition, no generally accepted or evidence-based guidelines are available for the specific therapeutic management of BS in this particular population and for the family screening of asymptomatic pediatric relatives of adult patients with BS and normal baseline ECG.
The purpose of the present study was to analyze our single-center experience of BS in children gathered over the last 20 years (since the first description of the syndrome). Particularly, our goal was to assess the clinical features, the based-device management, and the long-term follow-up of drug-induced BS in subjects ≤12 years of age at the time of diagnosis.
Since 1992, all consecutive patients diagnosed with BS by using an ajmaline challenge have been included in a registry and followed up in a prospective fashion. The ethics committee of the UZ Brussel-VUB approved the study protocol. A total of 505 patients with an ajmaline-induced diagnosis of BS were included in the registry from 1992 to 2013. In this group, 40 children were identified. Their data were used in the present study and compared with those of adult patients. Patients were considered as children if they were ≤12 years of age at the time of diagnosis (7). Physical examination, medical history, and baseline ECG were obtained, and underlying structural cardiac abnormalities were excluded in all patients. The recommendations of the Brugada consensus reports were used for establishing the diagnosis and for determination of candidacy for implantable cardioverter-defibrillator (ICD) therapy (8). Accordingly, ECGs were classified as Brugada coved-type (type I) or saddleback (type II) or normal. An ECG was considered diagnostic of BS if a coved-type ST-segment elevation ≥2 mm was documented in ≥1 lead from V1 to V3 in the presence or absence of a sodium channel blocker agent. Only patients with nondiagnostic baseline ECGs (normal ECG or Brugada type II ECG) were considered eligible for this study. All baseline and drug-induced 12-lead ECGs were recorded at a paper speed of 25 mm/s and amplitude of 10 mm/mV, with the right precordial leads positioned at the sternal margin of the third and fourth intercostal space. All ECGs were analyzed by 2 independent experienced electrophysiologists; in case of disagreement, a third physician was consulted. Electrophysiological study (EPS) was performed at the investigators' preference in asymptomatic patients with BS to assess risk stratification. A maximum of 3 ventricular extrastimuli with a minimum coupling interval of 200 ms was delivered from 1 ventricular site unless ventricular fibrillation (VF) or sustained ventricular tachycardia (VT) was induced.
Diagnosis of sinus node dysfunction (SND) was based on the correlation of symptoms with the presence of documented arrhythmias such as sinus bradycardia, sinus arrest, paroxysmal supraventricular tachycardia alternating with periods of bradycardia, or even asystole. Chronotropic incompetence, characterized by an impaired heart rate response to exercise, was considered as an additional manifestation of SND and was defined as failure to achieve 85% of the age-predicted maximum heart rate (9). Conventional 24- or 48-h Holter monitoring was performed in any case of suspected SND. Moreover, electrophysiological evaluation of SND was performed in all patients who underwent an EPS. Electrophysiological evaluation of SND included measurement of sinus node recovery time (SNRT), corrected SNRT (CSNRT = SNRT − sinus cycle length), SNRT/sinus cycle length × 100% (%SNRT), and sinoatrial conduction time estimated by using the method described by Narula et al. (10).
Ajmaline (1 mg/kg) was administered intravenously over a 5-min period to unmask the diagnostic ECG pattern of BS in case of nondiagnostic basal ECG. Drug administration was usually performed under drug sedation by injection of a single bolus of propofol in patients <5 years of age. The test was considered positive for BS only if coved-type I ECG was documented in ≥1 right precordial lead (V1 to V3). Ajmaline infusion was discontinued before reaching the target dose if QRS prolongation exceeded 30% compared with the baseline interval, when frequent premature ventricular beats or type 1 Brugada ECG occurred, or in the case of development of high-degree AV block. All ECGs were analyzed before and after ajmaline administration. Heart rate, PR interval, QRS duration, and QTc interval (determined by using Bazett's formula) were measured in milliseconds. Maximal ST-segment elevation was measured at the J point in the right precordial leads (V1 to V3), and the analysis of ST-segment elevation was performed in lead V1 and V2 at 40 ms from the J point. ECG measurements were repeated after ajmaline challenge. Ajmaline-induced sustained ventricular arrhythmia (VA) was defined as the occurrence of VF or sustained VT (lasting at least 30 s, accompanied by syncope or requiring intervention for termination).
Genetic testing with sequence analysis of SCN5A was recommended for all children who had a diagnosis of BS. Genomic DNA was extracted from peripheral blood leukocytes by using standard protocols. If no mutation was identified, sequence analysis of other genes (e.g., CACNA1C, SCN1B, KCNE3, SCN3B) was considered. Mutation-specific genetic testing was recommended for family members and appropriate relatives, after identification of the BS-causative mutation in an index case. In this study, children having undergone genetic testing were only screened for mutation in the SCN5A gene.
The decision to place epicardial versus endocardial ICD leads and the appropriate location for the ICD generator was made based on the patient's size, age, and activity level. The choice between single- and dual-chamber devices was driven by the presence of previous episodes of supraventricular arrhythmias or the evidence of SND. The device was usually programmed to treat ventricular rates >200 beats/min, and a VT-monitoring zone was occasionally added. However, these settings were adjusted on the basis of the patient's clinical history and to avoid inappropriate ICD therapies during follow-up.
Follow-up of patients consisted of physical examination and ECGs performed at least every 6 months. Clinical data were regularly collected. Patients with ICDs underwent scheduled follow-up of the device at 1 and 3 months and thereafter every 6 months. Beginning in 2006, devices with home-monitoring capabilities were implanted either de novo or at battery change, in case of previous implantation, in all patients ≤12 years of age.
Data are presented as mean ± SD or as absolute values and percentages where appropriate. The chi-square test and the Fisher exact test were used to compare categorical variables. Continuous variables between the 2 groups were analyzed by using the unpaired or paired Student t test as appropriate. A p value <0.05 was considered statistically significant. A z-score was calculated by using mean ± SD values of the general population as reference values. Statistical analyses were conducted by using SPSS version 21 (IBM SPSS Statistics, IBM Corporation, Armonk, New York).
Among all patients with drug-induced BS included in our database, 40 individuals (8%) were ≤12 years of age (group I) and 465 (92%) were >12 years of age (group II) at the time of diagnosis. Baseline clinical characteristics and ECG parameters of the study population are shown in Table 1.
Patients in group I (60% male; mean age 8 ± 2.8 years; range 1 to 12 years) belonged to 32 different families. Family history of SD was present in 24 children (60%). There were 2 children (5%), aged 6 and 11 years, who presented with a previous episode of aborted SD due to VF. Aborted SD was the first clinical manifestation of the syndrome in both patients. No significant differences were found in the sex, family history of SD, or previous episodes of aborted SD between groups I and II.
Indications for ajmaline challenge were: family screening in 30 asymptomatic children (75%), syncope in 3 family members (8%), syncope in 1 child (2%) with Brugada type II ECG, syncope and family history of SD in 2 individuals (5%), syncope and documented atrial arrhythmias together with signs of SND in 2 subjects (5%), and aborted SD in the remaining 2 children (5%).
Eight children (20%) presented with syncope, and 30 patients (75%) were asymptomatic family members. No significant difference was found in the history of syncope between group I and group II. Children presented more frequently as asymptomatic family members compared with older patients (75% vs. 51%; p = 0.003). Mean age at the first symptom was 6 ± 5 years. Syncopal episodes occurred at rest in 7 children and during exercise in 1 child. In 2 cases (25%), syncope was associated with fever. No significant difference was found in the sex of symptomatic patients between the 2 groups (male 70% vs. 62%; p = 0.7). Among children with family history of SD, 4 patients (17%) presented with syncope before the diagnosis of BS, and none of them had had a previous episode of aborted SD. However, among children with no family history of SD, 5 (31%) presented with syncope or aborted SD. A family history of SD in children was not significantly associated with the presence of symptoms before the diagnosis of BS (17% vs. 31%; p = 0.44).
Two children (5%) had previous documented episodes of atrial fibrillation (AF) and 1 child (2.5%) had atrial flutter. Three children (7.5%) presented with SND. History of sustained atrial arrhythmias (AF or atrial flutter) was comparable between groups (7.5% vs. 7.1%; p = 0.92). Children presented more frequently with signs of SND compared with individuals >12 years of age (7.5% vs. 1.5%; p = 0.04). Furthermore, a history of AF and SND was more frequently present in symptomatic children compared with asymptomatic children (30% vs. 0%; p = 0.01). Before the diagnosis of BS, no episode of second- or third-degree AV block was documented in any patient ≤12 years of age.
Thirty-four children (85%) presented with a normal baseline ECG. Three patients (7.5%) presented with baseline Brugada type II ECG. No child had left bundle branch block on baseline ECG, 1 child (2%) presented with incomplete right bundle branch block, and another child (2%) presented with complete right bundle branch block. Patients ≤12 years of age more frequently had a normal baseline ECG compared with older individuals (85% vs. 52%; p < 0.01). No significant differences were found in the baseline QRS duration or QTc interval. Conversely, baseline PR interval was significantly longer in patients >12 years of age compared with younger subjects (173 ± 32 ms vs. 140 ± 28 ms; p < 0.01). One child (2%) presented with a baseline PR interval >200 ms. A statistically significant difference was found in the percentage of patients with baseline first-degree AV block (>200 ms) between groups I and II (2% vs. 13%; p = 0.05).
An EPS was performed for risk stratification purposes or suspected SND in 24 children (60%). The mean HV interval of these patients was 40.4 ± 4.2 ms. Sustained VAs were induced, during programmed ventricular stimulation (PVS), in 2 children (8%). Rate of episodes of inducible sustained VAs during PVS was higher in group II, although no statistically significant difference was found between the 2 groups (8% vs. 24%; p = 0.08). Moreover, AF was easily inducted during incremental atrial pacing in 2 children (5%). A total of 19 genetic tests (47%) were obtained, and 4 (21%) had positive results for the following mutations in the SCN5A gene: (c.[3695G>A]+[=] (p.R1232Q), (c.[4813+6_4819+9dupGGGT]+[=], (c.[2632C>T]+[=] (p.[R878C]+[=]), (c.[2989G>A]+[=] (p.A997T).
From 1992 to 2013, a total of 169 individuals ≤12 years of age underwent an ajmaline challenge for suspected BS. Among them, ajmaline challenge revealed a Brugada ECG type 1 in 40 children (24%). ECG parameters before and after ajmaline administration are shown in Table 2. After infusion of ajmaline, the PR interval, QRS duration, and QTc interval increased in all patients, with no significant differences between the 2 groups. During ajmaline challenge, 3 children (7%) experienced an episode of VF requiring external defibrillation for termination, and 1 child (3%) had a polymorphic VT terminated by a high dose of isoproterenol infusion (Fig. 1). Of note, ajmaline-induced sustained VAs were observed more frequently in children compared with older patients (10% vs. 1.3%; p = 0.005). None of them had any nonsustained VA before the sustained VA initiation, and no patient experienced any VA refractory to the first shock. Moreover, sustained VAs during ajmaline occurred more frequently in symptomatic children compared with asymptomatic subjects (30% vs. 3.3%; p = 0.04). No child had a prolongation of the HV interval after ajmaline administration to >100 ms. Furthermore, no advanced AV block was observed during ajmaline challenge.
Twelve children (30%) considered at high risk for the development of VAs underwent ICD implantation. Indications for ICD placement were: syncope in 6 patients, aborted SD in 2 subjects, sustained VA during ajmaline administration in 1 asymptomatic family member, and syncope and ajmaline-induced sustained VA in the remaining 3 children. Nine patients (75%) received a single-chamber device, and 3 children (25%) underwent a dual-chamber ICD implantation. Eleven children (92%) underwent an abdominal implantation, and 8 patients (67%) received an epicardial lead implantation. After ICD implantation, 2 children (17%) experienced a device-related early complication: an episode of pericarditis that occurred 1 month after epicardial lead placement and a dislocation of the abdominal generator that led to revision of the device 1 week after implantation.
After a mean follow-up time of 83 ± 51 months, none of the children with ajmaline-induced BS died suddenly (Table 3). One child (2%) had spontaneous sustained VAs. Moreover, a previously asymptomatic patient had a syncopal episode 3 years after the diagnosis and underwent an ICD implantation. Another child experienced 2 syncopal events, which were diagnosed as neurally mediated syncope. One child (2.5%) developed AF 2 years after being diagnosed with BS. Among children who had undergone an ICD implantation, 1 patient (8%) experienced an episode of appropriate shock due to VF. Furthermore, 4 children with ICD (33%) had inappropriate ICD shocks due to episodes of supraventricular tachycardia, consisting of AF in 2 cases and sinus tachycardia in 1 child, and noise on ventricular channel after lead fracture in another child.
During follow-up, 4 children (33%) experienced device-related complications: fracture of ventricular lead in 2 patients that led to replacement of the electrode, lead dislocation in 1 child that led to revision of the device, and device infection in the other child who underwent replacement of the device. Moreover, 1 child, who had experienced multiple inappropriate ICD shocks for drug-resistant AF with rapid ventricular response, underwent pulmonary vein isolation by means of cryoballoon ablation. Although nonsustained runs of AF were documented, the patient remained free from ICD shocks without antiarrhythmic therapy 12 months after the procedure. None of the children who experienced VAs during ajmaline challenge had further VA events during follow-up.
To our knowledge, this is the largest series of children with drug-induced BS. Moreover, this is the first report addressing the clinical features and the long-term follow-up of BS in this specific category of BS patients.
Clinical presentation of BS in childhood
Although BS is thought to be an inherited primary arrhythmia syndrome with autosomal dominant inheritance, it is rarely diagnosed in children. In fact, ECG penetrance in SCN5A mutation carriers has been shown to be considerably lower in children than in adults (17% vs. 100%) (11). Moreover, genetic and clinical heterogeneity of BS can lead some individuals with syncopal episodes to exhibit the Brugada type I ECG as well as a positive response to sodium channel blocker drugs in an age-dependent manner (12). In addition, in a single-family study of a SCN5A mutation causing both BS and long-QT syndrome, QT prolongation was recognized from birth onward, whereas ST-segment elevation became apparent only after 5 years of age (13). All these data suggest that although patients are born with the pathological mutation, both the symptoms and the ECG phenotype in the large majority of cases do not manifest during childhood. Age-dependent clinical and ECG manifestation of BS can be influenced by multiple factors, including hormonal, autonomic, and genetic substrates. In particular, testosterone may play a role as a potential hormone responsible for the age-dependent manifestation of BS phenotype, as suggested by the disappearance of Brugada type I ECG after surgical castration for prostate cancer (14). However, although infrequent, BS can present with an extremely severe manifestation in early childhood and can be a cause of unexplained sudden cardiac death in children (15). In 2007, Probst et al. (6) described a series of 30 patients <16 years of age affected by BS, and 13 of them presented with drug-induced type I ECG. Among the drug-induced BS patients, only 1 subject was symptomatic, and no male predominance was observed in the total cohort or in those with symptoms. In our study, 24% of children who underwent an ajmaline challenge for suspected BS had a positive response to the pharmacological test; they represented only 8% of all patients diagnosed with ajmaline-induced BS in the last 20 years, suggesting that response to ajmaline can also be age-dependent. Furthermore, 25% of our study population presented with symptoms (syncope or aborted SD). Although only subjects ≤12 years of age were considered as “children” to avoid any hormonal influence in the clinical and ECG manifestation of the syndrome, 60% of children and 70% of symptomatic children were male. Moreover, although 2 patients with previous aborted SD were both female, no significant difference was found in the sex of symptomatic patients between children and older patients. These data may suggest that testosterone or other hormonal factors could be involved in determining male predominance of BS in symptomatic children as well. Age-dependent clinical and ECG manifestation of BS in children should be investigated with further studies.
Supraventricular arrhythmias and SND are common arrhythmic disorders in adults with BS (16,17). In the present study, similar to the adult population, sustained atrial arrhythmias (e.g., AF, atrial flutter) were not uncommon findings, occurring in 7.5% of children with BS. Of note, children with BS more frequently had SND compared with older subjects. Moreover, symptomatic children presented more frequently with previous episodes of atrial arrhythmias and signs of SND compared with asymptomatic subjects. These data suggest that in children with SND or documented atrial arrhythmias and normal basal ECG, BS should be excluded, particularly if the child presents with syncope.
It has been shown that age exerts a significant influence on the duration of PR interval in normal subjects. In fact, as the child grows older, the average PR interval lengthens progressively from an average value of 0.114 s at 1 year of age to 0.15 s at 13 years of age (18). In our study, the baseline PR interval was significantly shorter in patients <12 years of age compared with older subjects, suggesting that age might also exert an influence on the duration of PR interval in patients with BS. Interestingly, the baseline PR interval of our study population was longer if compared with the expected PR interval for the same age group (mean z-score: 7.6 ± 16.4) (19). Moreover, in our study, 1 child (2.5%) presented with a PR interval >200 ms.
Although children with BS present less frequently with first-degree AV block compared with older patients, incidence of first-degree AV block seems to be higher in children with BS than in the general pediatric population (2.5% vs. 0.02%) (20). Because BS is a channelopathy caused by a loss of function of the sodium channel, it would not be surprising that conduction defects, including first-degree AV block, could coexist with the typical ST-segment elevation, regardless of the age of the patient (21). Hormonal influence may play a role in determining development of conduction defects in BS patients after puberty. Further specific studies are needed to confirm these findings.
Ajmaline challenge is an established tool to unmask the diagnostic Brugada ECG pattern in patients with suspected BS and nondiagnostic ECG (2). However, its value in unmasking BS and its safety in children have not been systematically investigated. Veltmann et al. (22) reported a positive response to ajmaline in 262 (39%) of 677 patients with a normal ECG and suspected BS. The mean age of this subgroup of patients was 44 ± 15 years, and 62% were male. Conversely, Rolf et al. (23) reported 23% of adult patients (mean age 42 years) with Brugada type I ECG after ajmaline challenge. In our study, BS was diagnosed after ajmaline challenge in 24% of children with suspected BS. Ajmaline is considered the best agent for unmasking BS, both because of the drug's kinetics and its strength of rate-dependent sodium channel–blocking effects. Moreover, its short half-life and brief duration of electrophysiological effects offer a clinical advantage compared with other antiarrhythmic drugs. Unfortunately, ajmaline is not available worldwide. Other drugs, such as flecainide or procainamide, can be used to reveal the Brugada type I ECG in these cases. However, flecainide has been shown to have a lower sensitivity to unmask the diagnostic Brugada ECG compared with ajmaline (2). A greater inhibition of Ito may render it less effective. In addition, flecainide needs longer monitoring of the patients due to its prolonged pharmacological effect. Moreover, procainamide, a class IA antiarrhythmic drug, displays a more rapid dissociation from the sodium channel and consequently a lower level of use-dependent sodium channel blockade.
In the study by Rolf et al. (23), occurrence of sustained VAs was reported in 1.3% of patients who underwent ajmaline challenge for suspected BS. All episodes of VAs reported occurred in patients in whom drug administration was not discontinued after the appearance of diagnostic Brugada ECG changes. Conversely, Veltmann et al. (22) reported an incidence of sustained VAs in 0.1% of patients. In a more specific BS population consisting of patients <16 years of age, Probst et al. (6) found no occurrence of adverse events during drug challenge. Conversely, in our study, ajmaline provoked sustained VAs in 4 children (10%), and 3 of them (75%) were symptomatic for syncope. Importantly, children <12 years of age exhibited a higher risk of experiencing an ajmaline-induced VA compared with older patients (10.0% vs. 1.3%; p = 0.005). The absence of events during ajmaline testing in the series by Probst et al. might be explained by the lower rate of symptomatic children (8%) having undergone ajmaline challenge compared with our study population (25%). Our data confirm the necessity, for this category of patients, of performing ajmaline challenge in a safe environment with life-support facilities available, especially when children present with a history of syncope.
Twelve (30%) of our study children were considered at high risk of arrhythmic events and underwent ICD implantation. Although the management of asymptomatic children with drug-induced BS is straightforward, the device-based therapeutic management of symptomatic children is challenging. Moreover, ICD implantation in this particular set of patients is not without potential problems, given the subjects' very young age. It has already been shown that the rate of lead-related problems in pediatric patients is high: 23% of children with a pacing device can, in fact, experience a lead failure (24). In our study, during a mean follow-up of 83 ± 51 months, 33% of children experienced device-related complications. Importantly, lead-related problems can give rise to inappropriate therapies with significant impact on the quality of life of children and relatives.
All large registries including patients with BS and syncope reported that 6% to 19% of patients experienced an arrhythmic event during a follow-up of 24 to 39 months (5,25,26). In adults with BS, clinical symptoms such as syncope or aborted SD or spontaneous Brugada type I ECG are associated with a higher risk of SD during the follow-up. Probst et al. (6) reported that 2 (7%) of 30 patients experienced documented VAs during the follow-up that led to appropriate shocks. Both patients were symptomatic, with syncope and manifestation of a spontaneous type I ECG. Furthermore, inappropriate ICD intervention was recorded in 1 patient (20%). In a previously reported series, the incidence of inappropriate shocks was only slightly lower than the incidence of appropriate shocks, ranging from 17% to 23% for primary prevention and up to 30% for secondary prevention. In our study, only 1 child (2%) with drug-induced BS and syncope had a documented sustained VA successfully terminated by appropriate ICD intervention during follow-up. However, 4 children with ICD (33%) had inappropriate shocks due to very rapid supraventricular arrhythmias in 3 patients and lead fracture in 1 child.
On the basis of these findings, the optimal management of BS in childhood remains challenging and, due to the considerable rate of inappropriate ICD interventions and potential device-related complications, it should be always individualized, taking into consideration patient's age, clinical history, and the family's wishes. For asymptomatic BS children, a clinical follow-up with 12-lead ECG should be performed every 6 months. In these patients, particular attention should be paid after puberty to reveal potential appearance of spontaneous Brugada type I ECG or symptoms. Moreover, because fever is an important trigger for ventricular arrhythmias in BS, antipyretic therapy should be promptly administered during any febrile episode, and parents should bring the child to the hospital for clinical evaluation, ECG, and monitoring of cardiac activity (6). A hospital stay should be considered whether fever causes Brugada type I ECG or appearance of VAs.
Although there is a psychological impact for the patient and the family, family history of SD has not been shown to be predictive of future arrhythmic events in adults with BS and seems to be of no prognostic value in children (27). Thus, asymptomatic children with a family history of SD do not have an indication to implant an ICD or to undergo an EPS for risk stratification purposes. A clinical follow-up with ECG should be performed every 6 months in these cases.
Conversely, ICD therapy, although associated with significant morbidity, should always be considered to prevent SD in children with BS who present with a syncopal episode, if no other cause of the syncope is found (8). The decision to perform an ICD implantation in this setting should always be made after a careful evaluation of the syncopal episode and the family's wishes, and it should be performed following the best implantation technique in accordance with the patient's age. For those patients with limited symptoms at a young age in whom the family does not want to adopt an active approach, quinidine therapy might be considered as an alternative to prevent arrhythmic death until the child grows sufficiently to safely undergo ICD implantation (28). However, systematic studies on this approach in children are lacking.
This was a single-center experience, conducted in a population of patients with heterogeneous clinical characteristics, and its analysis was retrospective. Moreover, EPS with PVS as well as genetic testing was not performed in all children. Finally, no drug challenge was repeated.
Similarly to that seen in adult patients, drug-induced BS in children is commonly associated with male sex, sustained atrial arrhythmias, and SND. Children seem to be a category of BS patients at higher risk of experiencing sustained VAs during ajmaline challenge. Moreover, in children with ICD, the rate of device-related problems, which can lead to electrode replacement or inappropriate shocks, is considerable and even higher than appropriate ICD interventions. On the basis of these findings, the optimal management of drug-induced BS in childhood should always be individualized, taking into consideration the patient's clinical history and the family's wishes.
Prof. Brugada reports educational grants from Medtronic, St. Jude Medical, and Biotronik. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- atrial fibrillation
- Brugada syndrome
- electrophysiological study
- implantable cardioverter-defibrillator
- programmed ventricular stimulation
- sudden death
- sinus node dysfunction
- ventricular arrhythmia
- ventricular fibrillation
- ventricular tachycardia
- Received November 24, 2013.
- Revision received February 15, 2014.
- Accepted February 26, 2014.
- American College of Cardiology Foundation
- Brugada P.,
- Brugada J.
- Priori S.G.,
- Napolitano C.,
- Gasparini M.,
- et al.
- Probst V.,
- Denjoy I.,
- Meregalli P.,
- et al.
- Williams K.,
- Thomson D.,
- Seto I.,
- et al.,
- StaR Child Health Group
- Antzelevitch C.,
- Brugada P.,
- Borggrefe M.,
- et al.
- Holden W.,
- McAnulty J.H.,
- Rahimtoola S.H.
- Narula O.S.,
- Shantha N.,
- Vasquez M.,
- Towne W.D.,
- Linhart J.W.
- Beaufort-Krol G.C.,
- van den Berg M.P.,
- Wilde A.A.,
- et al.
- Alimurung M.M.,
- Massell B.F.
- Davignon A.,
- Rautaharju P.,
- Boisselle E.,
- Soumis F.,
- Mégélas M.,
- Choquette A.
- Kyndt F.,
- Probst V.,
- Potet F.,
- et al.
- Veltmann C.,
- Wolpert C.,
- Sacher F.,
- et al.
- Rolf S.,
- Bruns H.J.,
- Wichter T.,
- et al.
- Brugada J.,
- Brugada R.,
- Antzelevitch C.,
- Towbin J.,
- Nademanee K.,
- Brugada P.
- Eckardt L.,
- Probst V.,
- Smits J.P.,
- et al.
- Sarkozy A.,
- Sorgente A.,
- Boussy T.,
- et al.
- Hermida J.S.,
- Denjoy I.,
- Clerc J.,
- et al.