|
|
Post by pbruss on Jun 26, 2014 10:11:00 GMT -5
exactly. type 2 brugada. saw this kid at Lima. chesk out below for Up Tt Date for review
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: May 2014. | This topic last updated: Feb 07, 2014.
INTRODUCTION — The vast majority of cases of sudden cardiac arrest (SCA) and sudden cardiac death (SCD), due to ventricular fibrillation, are associated with structural heart disease, particularly coronary heart disease. SCA in the apparently normal heart is an uncommon occurrence, accounting for 5 to 10 percent of SCA cases. (See "Pathophysiology and etiology of sudden cardiac arrest".)
Some causes of SCA in patients with apparently normal hearts have been identified and include:
●Brugada syndrome
●Congenital long QT syndrome (LQTS) (see "Clinical features of congenital long QT syndrome")
●Acquired LQTS with polymorphic ventricular tachycardia (VT)
●Catecholaminergic polymorphic VT (see "Catecholaminergic polymorphic ventricular tachycardia and other polymorphic ventricular tachycardias with a normal QT interval")
●Idiopathic VT (see "Monomorphic ventricular tachycardia in the absence of apparent structural heart disease")
●Idiopathic ventricular fibrillation
●Short QT syndrome (see "Short QT syndrome")
●Commotio cordis (see "Commotio cordis")
The Brugada syndrome and the related disorder, sudden unexpected nocturnal death syndrome (SUNDS), will be reviewed here. Other causes of SCA in normal hearts are discussed elsewhere. (See "Sudden cardiac arrest in the absence of apparent structural heart disease".)
DEFINITION — The Brugada syndrome is an autosomal dominant genetic disorder with variable expression characterized by abnormal findings on the surface electrocardiogram (ECG) in conjunction with an increased risk of ventricular tachyarrhythmias and sudden cardiac death. Typically, the ECG findings consist of a pseudo-right bundle branch block and persistent ST segment elevation in leads V1 to V3 (waveform 1), although isolated cases have described similar findings involving the inferior ECG leads [1-4]. (See 'ECG patterns' below.)
Brugada pattern versus Brugada syndrome — Two terms, distinguished by the presence or absence of symptoms, have been used to describe patients with the typical ECG findings of a pseudo-right bundle branch block and persistent ST segment elevation in leads V1 to V3:
●Patients with typical ECG features who are asymptomatic and have no other clinical criteria are said to have the Brugada pattern. (See 'Diagnostic criteria' below.)
●Patients with typical ECG features who have experienced sudden cardiac death or a sustained ventricular tachyarrhythmia, or who have one or more of the other associated clinical criteria, are said to have the Brugada syndrome. Patients with ventricular premature beats or nonsustained ventricular tachycardia, however, are generally not considered to have Brugada syndrome but only the Brugada pattern. (See 'Diagnostic criteria' below.)
Persons with either the Brugada pattern or the Brugada syndrome can have identical findings on the surface ECG. (See 'ECG patterns' below.)
While three different patterns of ST elevation were initially described (figure 1) and were used in clinical practice for years, subsequent consensus is that there are two distinct patterns of ST elevation [5-7].
●In the classic Brugada type 1 ECG, the elevated ST segment (≥2 mm) descends with an upward convexity to an inverted T wave. This is referred to as the "coved type" Brugada pattern.
●In the type 2 pattern (combined from the original designation of types 2 and 3 patterns), the ST segment has a "saddle back" ST-T wave configuration, in which the elevated ST segment descends toward the baseline, then rises again to an upright or biphasic T wave.
Moving the right precordial chest leads up to the second or third intercostal space or using bipolar chest leads [8] may increase the sensitivity of detecting these abnormalities [6,9]. In a study of 98 men with a family member with a type I Brugada ECG, those with a type I Brugada ECG pattern only in high chest leads had a similar rate of cardiac events during >1 year of follow-up as those with type 1 Brugada ECG with standard positioning of chest leads [10]. However, the incidence of false-positive results needs to be better defined in larger studies.
The widened S wave in left lateral leads that is characteristic of RBBB is absent in most patients with BS. This observation suggests that there is a high takeoff of the ST segment in the right precordium (ie, a "J" wave rather than a true RBBB) [4].
QT interval prolongation may be seen in the right precordial leads [11]. The degree of prolongation is usually modest, but some patients have genetic abnormalities that cause both BS and long QT syndrome [12-14].
EPIDEMIOLOGY
Prevalence — The prevalence of the typical ECG changes of the Brugada pattern has been evaluated in a number of different populations. Studies in heterogeneous populations suggest that the majority of affected individuals are of Asian descent [4].
●In two reports from Japan, the prevalence was 0.7 and 1.0 percent [15,16]; 0.12 to 0.16 percent of the Japanese population have type 1 (coved type) ST segment elevation [15,17,18].
●In a Finnish cohort, the prevalence of type 2 and 3 ST segment elevation was 0.6 percent; no type 1 patients were found in a screen of over 3000 apparently healthy individuals [19].
●In two samples of urban populations in the United States, the prevalence was 0.4 and 0.012 percent, respectively [20].
The prevalence of Brugada Syndrome among patients with Brugada pattern ECGs has not been well studied, but a meta-analysis of 30 published reports of patients with Brugada ECGs demonstrated a 10 percent event rate at 2.5 years [21]. The prevalence of the Brugada pattern is much greater in patients who present with apparent idiopathic VF (3 to 24 percent in one series of 37 patients, depending upon the diagnostic criteria used) [22]. (See "Sudden cardiac arrest in the absence of apparent structural heart disease", section on 'Idiopathic VF'.)
Gender — The Brugada pattern is much more common in men than in women, being as much as nine times higher in one analysis, and men had a higher rate of syncope and sudden death in a large prospective registry study [18,23]. Reasons for the prominent male predominance in an autosomal dominant disorder are unclear. Animal models suggest that the impact of testosterone on ion currents, particularly outward potassium currents, may contribute to the increased incidence of clinical manifestations of Brugada syndrome in males [24,25]. (See 'Genetics' below.)
Age at diagnosis — Brugada syndrome is usually diagnosed in adulthood. In two of the larger series of Brugada syndrome, the average patient age was 41 years [26,27]. While the Brugada syndrome is rarely diagnosed in children, the clinical features of Brugada syndrome in childhood were illustrated in a cohort of 30 children diagnosed at 13 referral centers in Europe [28]. Because the data are limited, the optimal approach to the management of children with Brugada pattern or Brugada syndrome is not known. (See 'Treatment' below.)
PATHOGENESIS — A variety of factors may contribute to the clinical manifestations of Brugada syndrome including right ventricular abnormalities, mutations in the cardiac sodium channel gene SCN5A, autonomic tone, and the use of cocaine and psychotropic drugs.
Genetics — The Brugada syndrome demonstrates autosomal dominant inheritance with variable expression. Genetic analysis has led to the identification of causative mutations in the SCN5A gene, encoding subunits of a cardiac sodium channel. Reasons for the variable expression of Brugada syndrome are not completely understood, although compound heterozygosity had been described in one family [29].
Sodium channel gene — Mutations in SCN5A, the gene that encodes the alpha subunit of the cardiac sodium channel gene, have been found in 18 to 30 percent of families with Brugada syndrome [6,26,30,31]. The gene locus is on chromosome 3p21-24.
The SCN5A mutations seen in Brugada syndrome are "loss of function" mutations and result in a variety of abnormalities in sodium channel activity including failure of expression, alterations in the voltage and time dependence of activation, and accelerated or prolonged recovery from inactivation [6]. In addition, mutations may explain the ability of sodium channel blockers to expose the ECG changes in some patients with this disorder [2,6,32-34]. (See 'Diagnostic criteria' below.)
The defective myocardial sodium channels reduce sodium inflow currents, thereby reducing the duration of normal action potentials. In addition, a prominent transient outward current, called I(to), in the right ventricular epicardium further shortens the action potential [35].
The relationship between sodium channel abnormalities and ST segment elevation is not fully understood. The ventricular myocardium is composed of at least three electrophysiologically distinct cell types: epicardial, endocardial, and M cells. The ST segment elevation and T wave inversions seen in the right precordial leads in Brugada syndrome are thought to be due to an alteration in the action potential in the epicardial and possibly the M cells, but not the endocardial cells [4,35-37]. The resulting dispersion of repolarization across the ventricular wall, which is most pronounced in the right ventricle, results in a transmural voltage gradient that is manifested in the electrocardiogram as ST segment elevation.
The means by which the SCN5A mutation may predispose to ventricular tachyarrhythmias is discussed below, but like the ST segment elevation, VT and VF may be caused by heterogeneity of the cardiac action potential, both across the three layers of myocardial cells and within the epicardium itself.
Related disorders — Mutations in the SCN5A gene have also been associated with other electrophysiologic abnormalities:
●Isolated AV conduction defect
●Congenital long QT syndrome type 3 (LQT3)
●Congenital sick sinus syndrome
●Familial dilated cardiomyopathy with conduction defects and susceptibility to atrial fibrillation
The differences in clinical manifestations are probably due to differences in the electrophysiologic abnormalities induced by the specific mutations [38-42]. Certain SCN5A mutations have been associated with an "overlap" syndrome, with affected patients exhibiting sick sinus syndrome or complete heart block as well as Brugada syndrome [41,42]. (See "Etiology of atrioventricular block", section on 'Familial disease' and "Genetics of congenital and acquired long QT syndrome", section on 'LQT type 3' and "Genetics of dilated cardiomyopathy" and "Manifestations and causes of the sick sinus syndrome", section on 'Childhood and familial disease'.)
Most of the mutations in Brugada syndrome are found at sites other than those known to contribute to the long QT syndrome [30,38]. One exception is a 1795insD mutation (insertion of aspartic acid) in the C terminus, which can cause both the long QT and Brugada syndrome as a result of its interaction with a heterogeneous physiologic substrate [12,13]. In another family, the mutation was associated with Brugada syndrome, long QT syndrome, and a conduction defect [14].
Further support for an overlap between Brugada syndrome and LQT3 comes from a report of 13 patients with LQT3 who received intravenous flecainide [40]. Although shortening of repolarization and the QT interval occurred in 12 of these patients, six (46 percent) developed ST segment elevation in V1 through V3, compatible with Brugada syndrome. (See "Genetics of congenital and acquired long QT syndrome".)
Additional loci — Since only a minority of affected families have an identified abnormality of SCN5A, it is possible that additional genetic abnormalities may produce the phenotypic characteristics of Brugada syndrome.
●Cardiac calcium channel gene – In a series of 82 probands with a clinical diagnosis of Brugada syndrome, seven individuals (8.5 percent) were found to have mutations in the alpha1 or beta2 subunit of the cardiac L-type calcium channel [43]. Three of these patients had a unique phenotype in that in association with the typical ECG findings of Brugada syndrome, they also had shortened QT intervals (≤360 msec). The relationship of this disorder to the usual form of Brugada syndrome and to short QT syndrome remains to be defined. (See "Sudden cardiac arrest in the absence of apparent structural heart disease", section on 'Short QT syndrome'.)
●A locus on chromosome 3p22-25 has been identified in a large family with an autosomal dominant syndrome similar to Brugada syndrome (RBBB and ventricular arrhythmias) [44]. The mutation is also associated with progressive conduction disease. Compared to patients with SCN5A mutations, affected members of this family had a good prognosis with a very low incidence of SCD. Also in contrast to mutations in the sodium channel gene, characteristic ECG changes were not exposed by infusions of procainamide.
A specific disease-causing gene at this locus has not yet been identified, which limits full characterization of this disorder and its relationship to the usual form of Brugada syndrome.
●Mutations in KCNE3 and KCNE2 causing gain of function in the transient outward current (Ito) and Brugada Syndrome have been identified in rare probands [45,46]. As discussed below, increased Ito current may lead to arrhythmias in Brugada.
●Other sodium channel mutations – Other mutations that decrease the sodium channel current have been identified in isolated kindreds with Brugada syndrome. These include a mutation in SCN1B, an accessory subunit that interacts with the sodium channel and is also associated with conduction system disease [47], and a mutation in GPD1-L, a gene that affects trafficking of the sodium channel [48].
Microscopic structural abnormalities and fibrosis — Brugada syndrome is not usually associated with structural heart disease. Standard cardiac testing, including echocardiography, stress testing, and cardiac magnetic resonance imaging often reveal no abnormalities. However, it is probably more accurate to categorize Brugada syndrome as a disorder that occurs in hearts that are apparently normal since there is some evidence that subtle structural or microscopic abnormalities occur, including dilation of the right ventricular outflow tract and localized inflammation and fibrosis [49-53].
Supporting a pathogenic role of fibrosis in Brugada syndrome, a mouse model of heterozygous SCN5A knockout revealed age-dependent fibrosis and marked slowing of conduction velocity in the right ventricle [50]. Similarly, evaluation of an explanted heart from a transplant recipient with Brugada syndrome revealed microscopic fibrosis and conduction abnormalities [51].
Further evidence of microscopic abnormalities in Brugada syndrome comes from a series of 18 patients who underwent endomyocardial biopsy [49]. Although noninvasive evaluation was normal in each patient, all had evidence of microscopic structural abnormalities, including signs of RV myocarditis in 14. The ECG changes resolved at follow-up in 8 of the 14 patients with signs of RV myocarditis, raising the possibility that the Brugada pattern ECG seen in these patients at presentation may have been a manifestation of RV myocarditis rather than an intrinsic cardiac ion channel abnormality.
Patients with spontaneous type 1 ECGs were found to have significant enlargement of the right ventricular outflow tract on cardiac MRI compared with patients with drug-induced type 1 ECGs and controls as well as mildly lower left and right ventricular ejection fractions. The differences were not large enough to aid in diagnosis but provided further evidence of subtle structural abnormalities [54].
Ventricular arrhythmias and phase two reentry — Ventricular arrhythmias may result from the heterogeneity of myocardial refractory periods in the right ventricle. This heterogeneity arises from the presence of both normal and abnormal sodium channels in the same tissue, and from the differential impact of the sodium current in the three layers of the myocardium (see 'Sodium channel gene' above) [35,36,55].
Within the epicardium, the juxtaposition of myocytes with different refractory periods can produce the triggers that initiate sustained arrhythmias (eg, closely-coupled premature beats) via a unique type of reentry called phase two reentry. In cardiac myocytes with defective sodium channels, initial depolarization is blunted (phase zero), and the counterbalancing effect of I(to) (phase 1) may be more significant. This phenomenon is more dramatic in the epicardium where I(to) currents are greater. In combination, this results in less initial depolarization and reduced activation of the calcium channels that maintain the depolarized state during phase two. Thus, phase two of the cardiac action potential can be dramatically shortened.
The cells with impaired sodium channel function may fail to propagate the action potential, resulting in localized conduction block. However, due to the abbreviation of phase two, these same cells have a much shorter refractory period and recover excitability before the surrounding cells. The combination of localized conduction block and a shortened refractory period provides the substrate for localized reentry, which, in this case, is referred to as phase two reentry. The closely-coupled ventricular premature beats that result from phase two reentry may precipitate sustained ventricular arrhythmias. Optical mapping studies have supported this mechanism of initiation of polymorphic ventricular tachycardia and ventricular fibrillation in a canine model of Brugada syndrome [56]. This mechanism is also seen in flecainide-induced arrhythmias [57] and is similar to the mechanism of arrhythmogenesis during myocardial ischemia.
Other factors also may be important. Subtle structural abnormalities (eg, interstitial fibrosis or inflammation) in combination with reduced sodium currents could produce localized delay of impulse conduction [50]. The possible significance of conduction delay is less well established than action potential heterogeneity, and the issue is complicated by the possibility of overlap with other arrhythmia syndromes, particularly arrhythmogenic right ventricular cardiomyopathy. (See 'Microscopic structural abnormalities and fibrosis' above and 'Brugada ECG pattern in ARVC' below.)
Autonomic tone — An imbalance between sympathetic and parasympathetic tone may be important in the pathogenesis of Brugada syndrome, as suggested by the nocturnal occurrence of the associated tachyarrhythmias and the alteration of typical ECG changes by pharmacologic modulation of autonomic tone [58-60].
Further support for the role of autonomic dysfunction comes from a study of 17 patients with Brugada syndrome who underwent scanning with iodine-123-metaiodobenzylguanidine (MIBG), a radiolabeled guanethidine analog that is actively taken up by sympathetic nerve terminals [59]. A segmental reduction in MIBG uptake was seen in 8 of the 17 patients, but in none of 10 controls.
Augmentation of ST elevation ≥0.05 mV in leads v1-v3 during recovery from exercise is seen in some patients with Brugada syndrome and has been associated with worse arrhythmic outcomes. In a study of 93 patients with Brugada syndrome, 37 percent had augmentation of ST elevation in exercise recovery, and during follow-up, 44 percent of these patients versus 17 percent of patients without ST augmentation had arrhythmic events [61]. The mechanism may be a response to parasympathetic reactivation during recovery from exercise.
Fever — Data from a retrospective review of 111 patients with Brugada syndrome suggest that fever is a trigger for ECG changes and cardiac arrest [62]. In 24 of these patients with ECGs recorded during both fever and normothermia, fever was associated with Brugada pattern ECG changes. Fever was present in 4 of 22 patients with cardiac arrest.
Cocaine abuse — The ECG findings of Brugada pattern can be transiently induced by cocaine use [63]. Cocaine acts like a class I antiarrhythmic agent, producing local anesthetic effects via sodium channel blockade in the heart; this could explain the relation to the Brugada pattern. (See "Evaluation and management of the cardiovascular complications of cocaine abuse".)
Psychotropic drugs — Other drugs that block cardiac sodium channels have been associated with a transient Brugada pattern on the ECG, including overdoses with neuroleptic drugs or cyclic antidepressants [64,65]. In one report, a Brugada pattern was seen in 15 of 98 cases (15.3 percent) of a cyclic antidepressant overdose [65]. One patient with the Brugada pattern and one without died of refractory ventricular fibrillation.
CLINICAL FEATURES — The Brugada syndrome combines the typical electrocardiogram (ECG) findings of the Brugada ECG pattern with a presentation suggesting ventricular arrhythmias. Most clinical manifestations of the Brugada syndrome are related to life-threatening ventricular arrhythmias. Sudden cardiac arrest may be the initial presentation of Brugada syndrome in as many as one-third of patients. Patients may also present with an episode of syncope with features suggestive of a tachyarrhythmic cause of the syncope. Palpitations related to ventricular tachyarrhythmia are not common in the Brugada syndrome, but patients may present with palpitations related to atrial fibrillation, which is associated with Brugada syndrome and may be the first presentation of the disease [66]. Nocturnal agonal respiration is also described and is part of the diagnostic criteria.
ECG patterns — Persons with Brugada pattern findings on a surface ECG have some form of a pseudo-right bundle branch block and persistent ST segment elevation in leads V1 to V3 (waveform 1). However, two different patterns of ST elevation have been described (table 1 and figure 1) [5,6].
●In the classic Brugada type 1 ECG, the elevated ST segment (≥2 mm) descends with an upward convexity to an inverted T wave. This is referred to as the "coved type" Brugada pattern.
●In the type 2 pattern (combined from the original designation of types 2 and 3 patterns), the ST segment is ≥2 mm elevated and has a "saddle back" ST-T wave configuration, in which the elevated ST segment descends toward the baseline but remains at least 0.5 mm above the isoelectric baseline and then rises again to an upright or biphasic T wave.
Moving the right precordial chest leads superiorly to the second or third intercostal space or using bipolar chest leads may increase the sensitivity of detecting these abnormalities and should be performed when there is a doubt about the diagnosis [6,8,9]. In a study of 98 men with a family member with a type I Brugada ECG pattern, those with a type I Brugada ECG pattern only in high chest leads had a similar rate of cardiac events during >1 year of follow-up as those with type 1 Brugada ECG with standard positioning of chest leads [10]. However, the incidence of false-positive results needs to be better defined in larger studies.
The widened S wave in left lateral leads that is characteristic of RBBB (waveform 2) is absent in most patients with Brugada patterns on ECG. This observation suggests that there is a high takeoff of the ST segment in the right precordium (ie, a "J" wave rather than a true RBBB) [4]. Complete RBBB, however, can mask the Brugada ECG findings [67-69]. In such patients, the Brugada pattern may be demonstrated following resolution of the RBBB or following drug challenge or right ventricular pacing [67].
QT interval prolongation may be seen in the right precordial leads [11]. The degree of prolongation is usually modest, but some patients have genetic abnormalities that cause both Brugada pattern and long QT syndrome [12-14]. (See 'Sodium channel gene' above.)
In some patients, the characteristic ECG changes of the Brugada pattern are transient or variable over time. In one series of 43 patients with Brugada pattern, in whom 310 ECGs were obtained over a median follow-up of 18 months, the following findings were noted [70]:
●Among 15 patients with a spontaneous type 1 ECG at presentation, 14 had at least one non-diagnostic (type 2, 3 or normal) ECG during follow-up.
●Among 28 patients whose initial ECG was non-diagnostic, eight developed characteristic type 1 ECG abnormalities during follow-up.
Thus, fluctuations in the Brugada ECG pattern over time appear to be common.
Provoking factors — Characteristic ECG abnormalities may be exposed by a sodium channel blocker, such as flecainide, ajmaline, or procainamide, thereby identifying those at risk (table 2) [2,6,32-34]. In addition, flecainide can also induce QT prolongation that is primarily seen in the right precordial leads (V1 and V2) [11]. (See 'Drug challenge' below.)
Pacing, vagal maneuvers, and increased alpha-adrenergic tone also may provoke the typical ECG changes of BS [58,59]. Other factors that can unmask or modulate the Brugada ECG pattern are beta blockers, tricyclic or tetracyclic antidepressants, lithium, local anesthetics, fever, hypokalemia, hyperkalemia, hypercalcemia, and alcohol and cocaine toxicity (table 2) [6,71]. A website has been established that identifies drugs that have been associated with adverse events in BS patients [72]. The role of genetic predisposition with these factors is not clear, though a case report of bupivacaine-induced ECG changes was associated with an SCN5A mutation [6,73]. (See 'Autonomic tone' above and 'Cocaine abuse' above and 'Psychotropic drugs' above.)
The clinical significance of drug-provoked ECG changes in the absence of symptoms, family history of BS, or family with Brugada ECG is undetermined.
Sudden cardiac arrest and syncope — Sudden cardiac arrest (SCA) and syncope resulting from ventricular tachyarrhythmias are the most significant clinical manifestations of Brugada syndrome. SCA may be the initial presentation of Brugada syndrome in as many as one-third of patients. Arrhythmic events generally occur between the ages 22 and 65 and are more common at night than in the day and during sleep than while awake [2,60]. SCA in patients with Brugada syndrome is usually not related to exercise [74]. Stored electrograms from implantable cardioverter-defibrillators have shown that frequent spontaneous premature ventricular beats, which are identical in morphology to those that initiate ventricular fibrillation, are often seen before the onset of the arrhythmia [75]. Syncope is a common finding in patients with Brugada Syndrome, occurring in 28 percent of patients in one study, though it should be noted that in this study, 30 percent of the episodes of syncope were due to nonarrhythmic causes (eg, neurocardiogenic), and these patients had a benign prognosis [76].
Atrial fibrillation — Patients with Brugada syndrome are at increased risk of atrial arrhythmias, most notably atrial fibrillation (AF) [77-79]. The incidence of AF is 10 to 20 percent in patients with Brugada syndrome, and the presence of AF has been associated with increased disease severity and a higher risk of ventricular fibrillation [77,79]. As examples:
●Among 59 patients with Brugada syndrome and 31 matched controls who were followed for an average of three years, AF occurred in 12 (20 percent) of the Brugada syndrome patients but in none of the control subjects [77].
●In a series of 73 patients with Brugada syndrome, AF occurred in 10 (14 percent) [79]. Patients with AF had a higher incidence of syncope (60 versus 22 percent of patients without AF) and ventricular fibrillation (40 versus 14 percent).
●Among 611 patients with Brugada syndrome, the diagnosis of AF preceded the diagnosis of Brugada syndrome in 35 (5.7 percent). The diagnosis of Brugada syndrome was made in 11 patients after initiation of a class 1c antiarrhythmic agent (table 3) for treatment of AF.
These findings are consistent with a diffuse myocardial nature of the sodium channel abnormality.
Nocturnal agonal respiration — As noted, sudden cardiac arrest is more common at night in patients with the Brugada syndrome, and sleep disordered breathing appears to be more commonly seen in patients with Brugada syndrome [80]. A pattern of nocturnal agonal respiration with gasping breaths during sleep has been reported and may represent aborted cardiac arrhythmias. This is generally considered an ominous symptom that should be considered the equivalent of syncope or ventricular arrhythmias when evaluating the patient using diagnostic criteria. (See 'Diagnostic criteria' below.)
Asymptomatic patients — The risk of cardiac arrest is much lower in asymptomatic patients, although subgroups of asymptomatic patients with increased risk can be identified [26,27,81,82]. In a review of 547 patients with the type 1 Brugada ECG pattern, 422 of whom were asymptomatic [27], among the asymptomatic patients, two features were important determinants of arrhythmic risk:
●The presence of a type 1 ECG abnormality spontaneously versus only after drug challenge (see 'Drug challenge' below)
●Inducible ventricular tachyarrhythmia on EP testing
At a mean follow-up of 24 months, the following probabilities of arrhythmic events (SCD or documented VF) were reported (table 4):
●Among patients with a spontaneous type 1 ECG, event rates for those with positive and negative EP testing results were 14 and 1.8 percent, respectively.
●Among patients with the type 1 ECG abnormality only after drug challenge, event rates for those with positive and negative EP testing results were 4.5 and 0.5 percent, respectively.
In the FINGER study, neither spontaneous type 1 ECG nor positive EP studies were predictive of arrhythmic outcomes (0.8 versus 0.4 percent for spontaneous ECG and 1.1 versus 0.4 percent for positive EPS) [83]. The overall event rate for asymptomatic patients was quite low (0.5 percent per year).
A low risk of an arrhythmic event (5 percent by age 41) among asymptomatic patients who had ST elevation only with sodium channel blocker administration was also noted in the study of 200 patients [26].
For many truly asymptomatic patients, and particularly for those with only a drug-induced type 1 BS ECG, close clinical follow-up may be sufficient for management given the low overall risk of arrhythmic events.
DIAGNOSTIC TESTING AND RISK STRATIFICATION — Once the diagnosis of Brugada syndrome is suspected based on the clinical presentation and electrocardiogram (ECG) findings, additional testing may be considered to further confirm the diagnosis of Brugada syndrome and to provide an estimate of risk of ventricular arrhythmias and sudden cardiac death in the individual patient. In general, all additional diagnostic testing should be performed following consultation with an electrophysiologist or a general cardiologist with specific training and expertise in the diagnosis and management of the Brugada syndrome.
Among the available testing, we most commonly perform a drug challenge as part of the diagnostic evaluation. We do not routinely proceed with additional testing (ie, signal-average ECG, invasive electrophysiology testing, and genetic testing) in all patients but consider the need for each test on a patient-by-patient basis.
Drug challenge — Among patients with the type 2 Brugada ECG pattern, the type 1 Brugada ECG pattern can occasionally be unmasked by sodium channel blockers (eg, flecainide, procainamide, ajmaline, pilsicainide) [6,32-34]. The importance of unmasking the type 1 Brugada ECG pattern relates to its relevance in confirming the diagnosis of Brugada syndrome, particularly in patients without symptoms. However, not all patients with a type 2 Brugada ECG need to undergo drug challenge. In particular, our experts feel that drug challenge is not necessary in patients who have documented ventricular fibrillation, polymorphic ventricular tachycardia, unexplained syncope strongly suggestive of a tachyarrhythmia, or nocturnal agonal respiration. Most of these symptomatic patients will receive an implantable cardioverter-defibrillator regardless of the results of drug testing. (See 'Type 2' below and 'Treatment' below.)
●For patients whose resting ECG shows either the type 2 or 3 Brugada pattern and who have a family history of sudden cardiac death at less than 45 years of age and/or a family history of type 1 Brugada pattern ECG changes, we proceed with a drug challenge.
●For patients whose resting ECG shows either the type 2 or 3 Brugada pattern who are asymptomatic and have no family history of sudden cardiac death, we do not recommend a drug challenge.
While drug challenge can be helpful when positive, the reported sensitivity of pharmacologic challenge with these drugs has been variable, ranging from as low as 15 percent up to 100 percent [31,33].
One of several sodium channel blocking drugs can be used for the drug challenge, with no evidence that one is more effective than the others for making the diagnosis of Brugada syndrome. Recommended doses for the different drugs include [6]:
●Flecainide – 2 mg/kg over 10 minutes intravenously or 400 mg PO
●Procainamide – 10 mg/kg over 10 minutes intravenously
●Ajmaline – 1 mg/kg over five minutes intravenously
●Pilsicainide – 1 mg/kg over 10 minutes intravenously
Indications for termination of the drug challenge include:
●Development of a diagnostic type 1 Brugada ECG pattern
●≥2 mm increase in ST segment elevation in patients with a type 2 Brugada ECG pattern
●Development of ventricular premature beats or other arrhythmias
●Widening of the QRS ≥30 percent above baseline
A drug challenge should only be performed by clinicians experienced in the administration of sodium channel blocking drugs and interpretation of ECGs. When performing a drug challenge, the patient should have continuous ECG monitoring. Sustained ventricular arrhythmias following drug challenge have been reported with all of the drugs used for the challenge [33,84-86]. In the largest cohort reported to date of 503 patients with unmasking of a Brugada pattern ECG following ajmaline administration, 9 patients (two percent) developed sustained ventricular arrhythmias requiring defibrillation [86].
Signal-averaged ECG — Signal-averaged ECG (SAECG) testing may be helpful in identifying patients with Brugada pattern ECG and an increased risk of future arrhythmic events. In a prospective study of 43 patients with Brugada syndrome, the presence of late potentials on signal-averaged electrocardiogram was significantly predictive of arrhythmic events. Patients with late potentials had a significantly higher arrhythmic event rate over 34 month follow-up compared with those without late potentials (72.4 versus 14.3 percent) [87]. (See "Technical aspects of the signal-averaged electrocardiogram" and "Clinical applications of the signal-averaged electrocardiogram: Overview".)
Electrophysiology testing — Invasive electrophysiology (EP) testing is not necessary in most patients with known or suspected Brugada syndrome.
●Patients with a Brugada ECG pattern and certain high-risk clinical features (ie, a history of sudden cardiac arrest [SCA], sustained ventricular tachyarrhythmias, or unexplained syncope) have an indication for implantable cardioverter-defibrillator (ICD) implantation, so while invasive EP testing may provide a small amount of additional information, it is unlikely to impact management [2,4,27,36,81,88]. (See 'ICD therapy' below.)
●Most studies have shown no benefit to invasive EP testing in patients with a Brugada ECG pattern who are otherwise asymptomatic.
The role of EP testing in asymptomatic patients remains an area of investigation and debate in which results have been inconsistent.
●Among 547 patients with an ECG diagnostic of type 1 Brugada syndrome and no prior cardiac arrest, invasive EP testing was performed at the discretion of the clinician in 408 patients, 163 of whom had an inducible sustained ventricular arrhythmia [27]. Inducible sustained ventricular tachyarrhythmia during invasive EP testing was a significant predictor of future adverse events.
●Among 369 asymptomatic patients from the FINGER registry who underwent invasive EP testing, inducible sustained ventricular tachyarrhythmia during EP testing showed no independent predictive value for future arrhythmic events [83].
●A prospective registry (308 consecutive patients) has demonstrated that, in patients with either spontaneous or induced type I ECG findings and no history of sudden cardiac arrest, programmed electrical stimulation was not a predictor of events during follow-up [89]. However, the presence of spontaneous type I ECG, syncope, ventricular effective refractory period <200 ms, and QRS fragmentation were significant predictors of arrhythmia over a median of 34 months.
Though invasive EP testing in asymptomatic patients for diagnostic and prognostic purposes has been recommended in the 2005 consensus statement on Brugada syndrome, the available data in asymptomatic patients are conflicting, and the majority of studies do not support EP testing. Therefore, we do not recommend EP testing in asymptomatic patients in most circumstances.
Genetic testing — Genetic testing for Brugada syndrome, which typically involves sequencing SCN5A, the gene encoding the alpha subunit of the cardiac sodium channel, is commercially available and can be useful in confirming the presence of a mutation in a patient with the suspected diagnosis of Brugada syndrome. In patients with a clinical diagnosis of Brugada syndrome, genetic testing may also allow family screening and risk stratification. However, the genetic and clinical heterogeneity of Brugada syndrome limit the utility of genetic testing, as the absence of a mutation in SCN5A does not exclude Brugada syndrome, and the presence of a mutation in SCN5A does not confirm the diagnosis of Brugada syndrome.
●Only 15 to 30 percent of patients diagnosed with Brugada syndrome have mutations in SCN5A [90]. This may reflect variations in the testing procedure since mutations in non-coding regions or alterations in splice sites are not always examined even though they can lead to abnormal sodium channel activity. In addition, there is evidence that mutations in other genes can give rise to this disorder [90]. (See 'Additional loci' above.)
●Not all patients with documented Brugada SCN5A mutations have Brugada syndrome. In one study, the average penetrance among 24 patients in four genotyped families was only 16 percent (one Brugada patient in each family) [31].
In light of these issues, we advise that genetic testing for Brugada syndrome be performed in conjunction with specialists who have expertise in this area.
DIAGNOSIS — The diagnosis of Brugada syndrome is most commonly made following a clinically significant event (ie, syncope, sudden cardiac death) in which the patient has the typical ECG findings associated with this entity. However, some patients may be diagnosed based on the presence of ECG findings and relevant family history of sudden cardiac death or Brugada ECG patterns. (See 'Clinical features' above and 'ECG patterns' above.)
The diagnosis of Brugada syndrome can be challenging, however, requiring a high degree of clinical suspicion. Both ECG and clinical features are important, as Brugada syndrome would not be diagnosed in the setting of ventricular arrhythmias and/or sudden cardiac death in the absence of the typical ECG manifestations. Conversely, the appearance of typical ECG changes alone without other clinical manifestations is considered to represent the Brugada ECG pattern but not the Brugada syndrome.
Diagnostic criteria — Because of the clinical variability in presentation and the different ECG manifestations which can be seen in the Brugada syndrome, diagnostic criteria have been proposed by professional societies from both Europe and North America [5,6]. In practice, most patients are diagnosed using the following diagnostic criteria:
Type 1 — In a report from the second consensus conference on the Brugada syndrome, it was proposed that type 1 Brugada syndrome should be strongly considered in patients who meet the following criteria [6]:
●Appearance of type 1 ST segment elevation (coved type) (figure 1) in more than one right precordial lead (V1 - V3) in the presence or absence of a sodium channel blocker, plus at least one of the following:
•Documented ventricular fibrillation
•Polymorphic ventricular tachycardia (VT)
•Family history of sudden cardiac death at less than 45 years of age
•Family history of type 1 Brugada pattern ECG changes
•Inducible VT during electrophysiology study
•Unexplained syncope suggestive of a tachyarrhythmia
•Nocturnal agonal respiration
Type 2 — The consensus report proposed that the diagnosis of Brugada syndrome should be strongly considered in patients with a type 2 Brugada ECG who meet both of the following criteria [6]:
●Appearance of type 2 ST segment elevation (saddle-back type) (figure 1) in more than one right precordial lead under baseline conditions, with conversion to type 1 following challenge with a sodium channel blocker, plus at least one of the following:
•Documented ventricular fibrillation
•Polymorphic ventricular tachycardia (VT)
•Family history of sudden cardiac death at less than 45 years of age
•Family history of type 1 Brugada pattern ECG changes
•Inducible VT during electrophysiology study
•Unexplained syncope suggestive of a tachyarrhythmia
•Nocturnal agonal respiration
The utility of lead V3 and the necessity of having more than one lead positive in the diagnosis of Brugada syndrome have been called into question by a study of 186 patients with spontaneous or drug-induced type 1 Brugada ECGs [91]. Among 376 ECGs, lead V3 provided no additional diagnostic information in any patient, and patients with ECGs with only one lead with a diagnostic pattern had similar outcomes to patients with 2 or 3 diagnostic leads.
DIFFERENTIAL DIAGNOSIS
Differential diagnosis of Brugada pattern ECG findings — The differential diagnosis for Brugada pattern ECG changes includes other conditions that result in apparent conduction and ST segment abnormalities in leads V1 to V3 on the ECG. Examples of such conditions include:
●Atypical right bundle branch block (see "Right bundle branch block", section on 'Electrocardiographic findings')
●Arrhythmogenic right ventricular cardiomyopathy (see 'Brugada ECG pattern in ARVC' below)
●Early repolarization (see "Early repolarization", section on 'ECG findings')
●Acute pericarditis (see "Clinical presentation and diagnostic evaluation of acute pericarditis", section on 'Electrocardiogram')
●Acute myocardial ischemia or infarction (see "Electrocardiogram in the diagnosis of myocardial ischemia and infarction")
●Hypothermia (see "ECG tutorial: Miscellaneous diagnoses", section on 'Hypothermia')
Brugada ECG pattern in ARVC — The Brugada pattern on ECG can be seen as an early subclinical manifestation of arrhythmogenic right ventricular cardiomyopathy (ARVC) [36]. ARVC is a genetic disorder, usually autosomal dominant, which primarily involves the right ventricle, as the right ventricular myocardium is typically replaced by fat, with scattered residual myocardial cells and fibrous tissue. (See "Arrhythmogenic right ventricular cardiomyopathy: Anatomy, histology, pathogenesis, and genetics".)
An association between ARVC and the Brugada pattern on ECG is suggested by a report of 96 victims of sudden cardiac death (SCD) who were ≤35 years and had a baseline ECG available [74]. Right precordial ST segment elevation with or without RBBB was present in 13 (14 percent); at autopsy, all but one had ARVC. However, this study was from southern Italy, where ARVC is an important cause of SCD. Furthermore, mutations in SCN5A have not been described in ARVC.
Patients with ARVC often have abnormalities in the right ventricle that can be seen on echocardiography or cardiac magnetic resonance imaging. In contrast, the vast majority of patients with Brugada syndrome do not have apparent structural heart disease on routine imaging studies [6]. (See "Clinical manifestations and diagnosis of arrhythmogenic right ventricular cardiomyopathy", section on 'Evaluation'.)
Differential diagnosis for VT or sudden death with a structurally normal heart — Additionally, for patients with clinical manifestations of ventricular tachyarrhythmias (ie, sudden cardiac death, syncope) and no apparent cardiac structural abnormalities, several conditions should be considered along with the Brugada syndrome, including:
●Congenital long QT syndrome (LQTS)
●Acquired LQTS with polymorphic ventricular tachycardia (VT)
●Catecholaminergic polymorphic VT
●Idiopathic VT
●Idiopathic ventricular fibrillation
●Short QT syndrome
●Commotio cordis
For most conditions in which VT or sudden cardiac death (SCD) occurs with no apparent cardiac structural abnormalities, the clinical scenario and the ECG findings can be used to exclude other conditions. As examples:
●Patients with VT or SCD associated with prolongation of the QT interval are more likely to have LQTS than Brugada syndrome, particularly if the patient has been exposed to medications which may prolong the QT interval. Similarly, patients with VT or SCD whose QT interval is markedly shortened are more likely to have short QT syndrome. (See "Clinical features of congenital long QT syndrome" and "Acquired long QT syndrome" and "Short QT syndrome".)
●Patients who experience VT or SCD in the setting of exertion are more likely to have catecholaminergic polymorphic VT than Brugada syndrome, in which symptomatic tachyarrhythmias are more likely to occur at rest. (See "Catecholaminergic polymorphic ventricular tachycardia and other polymorphic ventricular tachycardias with a normal QT interval".)
●Patients with VT or SCD following blunt chest trauma are more likely to have experienced commotio cordis. (See "Commotio cordis".)
PROGNOSTIC FACTORS — The most important prognostic risk factor for patients with the Brugada ECG pattern or Brugada syndrome appears to be a history of ventricular tachyarrhythmias leading to sudden cardiac arrest (SCA) or syncope. Other less powerful predictors of future events may include atrial fibrillation, male gender, and a family history of SCA.
Patients with a previous history of SCA and those with a history of syncope (unexplained syncope suggestive of a tachyarrhythmia) are at increased risk for subsequent arrhythmic events compared with asymptomatic individuals [26,27,81-83]. In the largest reported series of 1029 patients (654 asymptomatic) with Brugada syndrome in the FINGER (France, Italy, Netherlands, Germany) Registry, when compared with asymptomatic patients, a history of SCA conferred an 11 times higher risk of arrhythmic event, while a history of syncope was associated with a 3.4 times higher rate of arrhythmic events [83]. Similarly, in a review of 334 patients with the Brugada ECG pattern (71 had presented after cardiac arrest [group A], 73 after a syncopal episode [group B], and 190 with ECG findings alone [group C]) who were followed for a mean of 33 months, a new arrhythmic event (SCA or VF) occurred in 62 and 19 percent of group A and B patients, while only 8 percent of group C patients had a first arrhythmic event (figure 2) [81].
Atrial fibrillation (AF) appears to occur more commonly in patients with the Brugada ECG pattern than in the general population. Additionally, patients with the Brugada ECG pattern who experience AF have a higher risk of future ventricular tachyarrhythmias. (See 'Atrial fibrillation' above.)
Male gender and a family history of SCA may also be markers of increased risk in the Brugada syndrome. In one analysis of 200 symptomatic and asymptomatic patients with Brugada syndrome, male gender and a family history of SCA were identified as risk factors for subsequent SCA [26]. However, neither characteristic had a high specificity (26 percent for male gender and 65 percent for family history). The increased risk of male gender has been noted by others [27].
Abnormal J waves in the inferolateral leads followed by a flat, horizontal ST segment morphology (as opposed to an ascending morphology) was associated with a higher incidence of cardiac events in a population of 460 symptomatic and asymptomatic patients with Brugada syndrome [92]. In this population, a QRS duration in lead V2 longer than 90 ms was also associated with cardiac events.
TREATMENT — Treatment for patients diagnosed with the Brugada syndrome is primarily focused around termination of any ventricular arrhythmias with an implantable cardioverter-defibrillator (ICD) (algorithm 1 and algorithm 2). Initial pharmacologic therapy for arrhythmia prevention has been tried in the Brugada syndrome with relatively little success, so ICD implantation should be the first line therapy for nearly all patients. However, patients with the Brugada syndrome who experience recurrent ventricular arrhythmias resulting in ICD shocks may require therapy with an antiarrhythmic drug in an effort to reduce the frequency of ICD shocks.
In contrast to patients with the Brugada syndrome, patients with only the Brugada ECG pattern do not require any specific therapy.
Patients with Brugada syndrome — For patients with the Brugada syndrome who have survived sudden cardiac arrest or those with a history of syncope which is felt to be due to ventricular tachyarrhythmias, we recommend implantation of an implantable cardioverter-defibrillator (ICD) rather than antiarrhythmic drug therapy. Therapy with an ICD is well-documented to be safe and highly effective at terminating ventricular tachyarrhythmias.
Antiarrhythmic drug therapy in patients with the Brugada syndrome who have survived sudden cardiac arrest or those with a history of syncope which is felt to be due to ventricular tachyarrhythmias may be considered in two circumstances:
●In patients who refuse ICD implantation or are not considered a candidate for ICD implantation due to reduced life expectancy or significant comorbidities, we suggest initial therapy with either quinidine or amiodarone.
●In patients with an ICD who have recurrent arrhythmias resulting in ICD shocks, we suggest therapy with amiodarone, although quinidine is also an option for these patients.
ICD therapy — Several studies have looked at the effectiveness of ICD therapy specifically in patients with the Brugada syndrome:
●In one early non-randomized study of 63 patients with the Brugada syndrome in which patients received either an ICD (35 patients), pharmacologic therapy (15 patients), or no specific therapy (13 patients) and were followed for nearly three years, 32 percent developed ventricular arrhythmias [93]. There were no deaths in the ICD group compared with mortality rates of 26 and 31 percent among those treated pharmacologically or not treated, respectively.
●Similarly, among 258 patients with Brugada syndrome in a multicenter registry who received an ICD and were followed for an average of 2.5 years, 69 patients (27 percent) received at least one appropriate ICD shock during follow-up [6].
The role of the ICD in patients with Brugada syndrome and a lower risk profile is less clear. In one series of 220 patients with type 1 Brugada ECG findings (spontaneous in 62 percent, inducible in 38 percent) in which 114 patients (52 percent) were asymptomatic at presentation, the asymptomatic patients received an ICD on the basis of an abnormal invasive electrophysiology study (99 patients) or a family history of SCD or nonsustained ventricular tachycardia (15 patients) [94]. At a mean follow-up of 38 months, the following findings were noted:
●Appropriate ICD shocks occurred in 8 percent of the overall population (2.6 percent per year). Total arrhythmic events over the three years were significantly more common in patients who had a history of SCA or syncope prior to ICD implantation (22 and 10 percent respectively, compared to 4 percent among those who were asymptomatic).
●The overall complication rate was 28 percent, with 45 patients (20 percent) experiencing inappropriate shocks.
Thus, in this heterogeneous cohort of BS patients, including a significant percentage of asymptomatic patients and patients with a provocable (as opposed to spontaneous) type 1 ECG, overall event rates were relatively low but were significantly higher in patients with a history of syncope or SCA.
Drug therapy — In contrast to the known benefits of ICD for the termination of ventricular arrhythmias and prevention of sudden cardiac death (SCD), there are no proven pharmacologic treatments for preventing SCD in the Brugada syndrome, although there are data suggesting a benefit from quinidine [95,96]. The potential efficacy of quinidine was illustrated in a report in which EP testing was performed on 25 patients with Brugada syndrome (15 symptomatic and 10 asymptomatic) before and after treatment with quinidine bisulfate (mean dose 1483±240 mg/day) [95]. Ventricular fibrillation was inducible in all patients at baseline but in only three patients after three to seven days of quinidine therapy. Quinidine treatment was continued in 19 patients for a mean of 56 months. None of these patients had an arrhythmic event, although two had non-arrhythmia-related syncope [6,35]. The beneficial effect of quinidine is postulated to be mediated by blockade of I(to), the transient outward current, that increases heterogeneity and may promote ventricular premature beats that act as the trigger for VT/VF [35].
Other class I antiarrhythmic drugs may be deleterious, particularly sodium channel blockers. As noted above, a sodium channel blocker, such as flecainide, ajmaline, or procainamide, can transiently induce the characteristic type 1 ECG changes [2,6,32-34]. In addition, sodium channel blockade can induce ventricular premature beats or ventricular tachycardia in patients with BS, particularly in symptomatic patients (six of 10 in one report), and T wave alternans [84]. (See 'Drug challenge' above.)
Amiodarone is the most effective agent for the prevention of ventricular tachyarrhythmias, although there are more potential side effects with its use than with most other antiarrhythmic agents. The efficacy of amiodarone is discussed in greater detail elsewhere. (See "Clinical uses of amiodarone".)
The administration of cilostazol, a phosphodiesterase inhibitor that impairs platelet aggregation and is approved for the treatment of intermittent claudication, may have a beneficial effect in patients with the Brugada syndrome by mediating an increase in calcium current and reduction in I(to) due to an increase in heart rate. In a case report of a 67 year-old man with BS who had daily early morning episodes of VF, the episodes were completely prevented by cilostazol, recurred when the drug was discontinued, and were again prevented when the drug was restarted [97]. Additional confirmatory data are required prior to recommending this therapy.
Asymptomatic patients with the Brugada ECG pattern — For patients with the Brugada ECG pattern who are otherwise asymptomatic and have none of the criteria which would suggest Brugada syndrome (ie, family history of sudden cardiac death or type 1 Brugada ECG pattern), we recommend no treatment. Specifically, there are no data to suggest the use of an ICD or antiarrhythmic drugs in this group of patients.
Recommendations of others — Based upon the high incidence of sudden cardiac arrest (SCA) in selected patients with the Brugada syndrome, several professional societies have discussed their approach to the treatment of patients with the Brugada syndrome [6,98-100].
●The 2008 American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/AHA/HRS) guidelines for device-based therapy of cardiac rhythm abnormalities included the following statements regarding ICD therapy in Brugada syndrome (with the assumption that patients have a reasonable expectation of survival with a good functional capacity for more than one year) [98]:
•There is evidence and/or general agreement supporting ICD implantation in all patients with Brugada syndrome and prior SCA.
•The weight of evidence/opinion supports ICD implantation in patients with Brugada syndrome who have a history of syncope.
•The weight of evidence/opinion supports ICD implantation in patients with Brugada syndrome and a history of ventricular tachyarrhythmia that did not result in SCA.
The implications of a positive family history of SCD are uncertain, and the 2008 ACC/AHA/HRS guidelines did not address the prognostic significance of SCA or sudden cardiac death in a family member with Brugada syndrome. (See 'Provoking factors' above.)
●The second consensus conference on Brugada syndrome, endorsed in 2005 by the Heart Rhythm Society and the European Heart Rhythm Association, recommended a somewhat more aggressive approach with ICD implantation for nearly all patients with the Brugada syndrome, including many with asymptomatic patients [6].
SCREENING OF FIRST-DEGREE RELATIVES — Since Brugada syndrome follows an autosomal dominant genetic pattern with variable penetrance, all first-degree relatives of patients with confirmed Brugada syndrome should undergo screening with a clinical history and 12-lead electrocardiogram (ECG). While provocative pharmacologic testing and genetic testing are available, we do not proceed with these tests as part of the screening process for the majority of patients. Because of relatively limited data regarding the best approach to screening in such patients, recommendations for screening in this setting are primarily based on expert opinion [98,100,101].
Clinical history should carefully screen for a history of syncope, and a 12-lead ECG should be performed and carefully scrutinized for findings characteristic of the Brugada ECG pattern.
●First-degree relatives with a history of syncope and a Brugada type I ECG meet the criteria for the diagnosis of Brugada syndrome and should be managed accordingly. (See 'Patients with Brugada syndrome' above.)
●First-degree relatives with no history of syncope but a Brugada type I ECG meet diagnostic criteria for Brugada syndrome without symptoms and should be managed accordingly. (See 'Diagnostic criteria' above and 'Patients with Brugada syndrome' above.)
●First-degree relatives with a concerning history of syncope but a normal-appearing ECG have an indeterminate screening result but may continue to have a high suspicion for the Brugada syndrome. Such patients should have ongoing screening with serial ECGs performed over three to four visits over the course of one to two years. First-degree relatives with indeterminate screening should also be considered for provocative testing with a pharmacologic challenge. Since the diagnostic ECG changes of Brugada syndrome can appear later in life in the fourth and fifth decade, symptomatic younger patients with a first-degree relative with Brugada syndrome should continue to receive annual ECGs. A negative drug challenge has a specificity of 94 percent and negative predictive value of 83 percent in a similar population, and therefore a negative test makes Brugada syndrome unlikely, and ongoing screening is not mandatory in such patients [34]
●First-degree relatives with no history of syncope and a normal ECG are considered to have a negative screening result and do not require ongoing surveillance.
In contrast to screening with history and ECG, which we recommend for all first-degree relatives of patients with Brugada syndrome, we do not recommend universal genetic testing since the genetic heterogeneity of Brugada syndrome results in a low sensitivity for finding a mutation. However, there are situations in which genetic testing of the proband patient may allow for more efficient screening of family members (eg, large numbers of first-degree relatives), in which case we consider proceeding with the genetic testing as an adjunct to the clinical and serial ECG screening. This strategy would involve testing the proband, then performing targeted genetic testing of family members only if testing of the proband is positive for a known associated mutation.
SUDDEN UNEXPECTED NOCTURNAL DEATH SYNDROME — A sudden unexpected nocturnal death syndrome (SUNDS, also called sudden unexpected death syndrome or SUDS) has been described in young, apparently healthy males from Southeast Asia; this syndrome has several names including lai tai (death during sleep) in Thailand, bangungut (to rise and moan in sleep followed by death) in the Philippines, and pokkuri (unexpected sudden cardiac death at night) in Japan [102-104].
A low serum potassium level may contribute to sudden cardiac arrest (SCA) in these patients [6]. It has been suggested that a high carbohydrate meal may precipitate SCA, perhaps by increasing the secretion of insulin which drives extracellular potassium into cells.
A relationship to Brugada syndrome was initially suggested by the observation that a majority of patients with SUNDS have the ECG manifestations of Brugada syndrome [104]. This association was confirmed by the finding that these patients have mutations in the same cardiac sodium channel gene, SCN5A, that is abnormal in Brugada syndrome [105].
Based upon these observations, it has been concluded that SUNDS and Brugada syndrome are phenotypically, genetically, and functionally the same disorder [6,105]. Thus, the management of these patients should be the same as that for classic Brugada syndrome (algorithm 1 and algorithm 2).
The DEBUT trial evaluated the role of an implantable cardioverter-defibrillator (ICD) compared with beta blockers in 66 patients who were considered definite or probable SUNDS survivors [106]. The trial was prematurely terminated after a mean follow-up of 24 months because of four deaths in the beta blocker arm, compared with none in the ICD arm; seven patients in the latter group had recurrent ventricular fibrillation that was appropriately terminated by the ICD. Similar benefits had been noted in a pilot study of 20 patients.
SUMMARY AND RECOMMENDATIONS
●The Brugada syndrome is an autosomal dominant genetic disorder with variable expression characterized by abnormal findings on the surface electrocardiogram (ECG) in conjunction with an increased risk of ventricular tachyarrhythmias and sudden cardiac arrest (SCA). Patients with typical ECG features who are asymptomatic and have no other clinical criteria are said to have the Brugada pattern, while those with typical ECG features who have one or more of the associated clinical criteria are said to have the Brugada syndrome. (See 'Definition' above.)
●The prevalence of the typical ECG changes of the Brugada pattern ranges from 0.1 to 1 percent of the general population, with males affected up to nine times more commonly than females. Among those with the Brugada ECG pattern, the prevalence of symptoms or other clinical features which would result in the diagnosis of Brugada syndrome is not known. (See 'Epidemiology' above.)
●Most clinical manifestations of the Brugada syndrome are related to life-threatening ventricular arrhythmias. SCA may be the initial presentation of Brugada syndrome in as many as one-third of patients. Patients may also present with an episode of syncope with features suggestive of a tachyarrhythmic cause of the syncope. Nocturnal agonal respiration is also described and is part of the diagnostic criteria. (See 'Clinical features' above and 'Diagnostic criteria' above.)
●Persons with Brugada pattern findings on a surface ECG have some form of a pseudo-right bundle branch block and persistent ST segment elevation in leads V1 to V3 (waveform 1). However, three different patterns of ST elevation have been described (table 1 and figure 1). (See 'ECG patterns' above.)
•In the classic Brugada type 1 ECG, the elevated ST segment (≥2 mm) descends with an upward convexity to an inverted T wave. This is referred to as the "coved type" Brugada pattern.
•The type 2 patterns have a "saddle back" ST-T wave configuration, in which the elevated ST segment descends toward the baseline and then rises again to an upright or biphasic T wave.
●Once the diagnosis of Brugada syndrome is suspected based on the clinical presentation and ECG findings, additional testing may be considered to further confirm the diagnosis of Brugada syndrome and to provide an estimate of risk of ventricular arrhythmias and SCA in the individual patient. Among the available testing, we most commonly perform a drug challenge as part of the diagnostic evaluation. We do not routinely proceed with additional testing (ie, signal-average ECG, invasive electrophysiology testing, and genetic testing) in all patients but consider the need for each test on a patient-by-patient basis. (See 'Diagnostic testing and risk stratification' above.)
●The diagnosis of Brugada syndrome is most commonly made following a clinically significant event (ie, syncope, SCA) in which the patient has the typical ECG findings associated with this entity. Because of the clinical variability in presentation and the different ECG manifestations which can be seen in the Brugada syndrome, diagnostic criteria proposed by professional societies are used in the diagnosis of most patients. (See 'Diagnosis' above.)
●The most important prognostic risk factor for patients with the Brugada ECG pattern or Brugada syndrome appears to be a history of ventricular tachyarrhythmias leading to SCA or syncope. Other less powerful predictors of future events may include atrial fibrillation, male gender, and a family history of SCA. (See 'Prognostic factors' above.)
●Treatment for patients diagnosed with the Brugada syndrome (algorithm 1 and algorithm 2) is primarily focused around termination of any ventricular arrhythmias with an implantable cardioverter-defibrillator (ICD).
•For patients with the Brugada syndrome who have survived sudden cardiac arrest or those with a history of syncope which is felt to be due to ventricular tachyarrhythmias, we recommend implantation of an ICD rather than antiarrhythmic drug therapy (Grade 1A).
•In patients who refuse ICD implantation or are not considered a candidate for ICD implantation due to reduced life expectancy or significant comorbidities, we suggest initial therapy with either quinidine or amiodarone (Grade 2C).
•In patients with an ICD who have recurrent arrhythmias resulting in ICD shocks, we suggest therapy with amiodarone (Grade 2C), although quinidine is also an option for these patients.
•For patients with the Brugada ECG pattern who are otherwise asymptomatic and have none of the criteria which would suggest Brugada syndrome (ie, family history of sudden cardiac death or type 1 Brugada ECG pattern), we recommend no treatment (Grade 1B).
●Since Brugada syndrome follows an autosomal dominant genetic pattern with variable penetrance, all first-degree relatives of patients with confirmed Brugada syndrome should undergo screening with a clinical history and 12-lead electrocardiogram (ECG). While provocative pharmacologic testing and genetic testing are available, we do not proceed with these tests as part of the screening process for the majority of patients. (See 'Screening of first-degree relatives' above.)
ACKNOWLEDGMENT — The authors and UpToDate would like to thank Dr. Duane Pinto and Dr. Mark Josephson, who contributed to earlier versions of this topic review.
|
|
