Clinical evaluation and current trends in the diagnosis and treatment of Brugada syndrome

Abaram Chesa Mankwe; Jyh-Ming Jimmy Juang

doi:10.4103/njc.njc_5_20

CASE REPORT

Year : 2020 | Volume : 17 | Issue : 2 | Page : 142-147

Clinical evaluation and current trends in the diagnosis and treatment of Brugada syndrome

Abaram Chesa Mankwe¹, Jyh-Ming Jimmy Juang²
¹ Division of Cardiology, Department of Internal Medicine, Federal Medical Centre, Yenagoa, Bayelsa State, Nigeria
² Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan

Date of Submission	22-Jan-2020
Date of Decision	05-May-2020
Date of Acceptance	18-Jun-2020
Date of Web Publication	13-Nov-2021

Correspondence Address:
Dr. Abaram Chesa Mankwe
Department of Internal Medicine, Federal Medical Centre Yenagoa, Bayelsa State
Nigeria

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/njc.njc_5_20

Abstract

Brugada syndrome (BrS) is a cardiac channelopathy associated with an increased risk of unexplained syncope, life-threatening ventricular arrhythmia, or sudden cardiac death. The patients with BrS often have the arrhythmia at rest or while asleep. It could also be triggered by fever or medications. About 15% of those with BrS have a family history of this condition. BrS is diagnosed by identifying ST segment elevation in leads V1–V2 with a right bundle branch block-like appearance of standard 12-lead electrocardiogram (ECG) placed in the fourth intercostal space. The ST segment elevation could also be unmasked or become more obvious by placing lead V1–V2 in the second and third intercostal spaces. In some patients, the ECG shows a prolonged PR interval but normal QTc interval. The first-line therapy for patients with BrS presenting with prior cardiac arrest or documented ventricular tachycardia is an implantable cardioverter-defibrillator (ICD). In the cases with recurrent ventricular arrhythmia or electrical storm, pharmacological therapy with quinidine is recommended as an adjunct to an ICD. This article is an overview of the clinical evaluation and current trends in the diagnosis and treatment of BrS.

Keywords: Brugada syndrome, electrocardiography, implantable cardioverter-defibrillator, sudden cardiac death

How to cite this article:
Mankwe AC, Juang JMJ. Clinical evaluation and current trends in the diagnosis and treatment of Brugada syndrome. Nig J Cardiol 2020;17:142-7

How to cite this URL:
Mankwe AC, Juang JMJ. Clinical evaluation and current trends in the diagnosis and treatment of Brugada syndrome. Nig J Cardiol [serial online] 2020 [cited 2023 Apr 2];17:142-7. Available from: https://www.nigjcardiol.org/text.asp?2020/17/2/142/330427

Introduction

Brugada syndrome (BrS) is an autosomal dominant genetic disorder presenting as syncope or sudden cardiac death (SCD) in patients with structurally normal hearts. It is named after the Spanish cardiologists Brugada and Brugada who described the condition in 1992.^[1],[2] The condition affects between 1 and 12 per 10,000 people,^[3],[4] and it is more common in those of Asian descent and in males than females with a male-to-female ratio of 8–10:1.^[5],[6],[7] Many patients with BrS are asymptomatic, but those with symptoms may have fainting spells or SCD due to life-threatening arrhythmia such as ventricular fibrillation (VF) or polymorphic ventricular tachycardia (VT). Those with BrS are also more likely to experience fast heartbeats due to less severe arrhythmias such as atrioventricular nodal re-entrant tachycardia.^[8],[9] The cardiac arrhythmia seen in BrS often occurs at rest or during sleeping, followed by drinking alcohol or a heavy meal.^[10] These situations are linked to periods when the vagal nerve is activated, referred to as periods of high vagal tone. Certain medications may also precipitate arrhythmias in patients with BrS and should be avoided by these patients.^[11] Symptoms for most patients manifest in their third or fourth decade; however, the disease can occur at any age. BrS is diagnosed by identifying characteristic patterns on an electrocardiogram (ECG).^[11] The pattern seen on the ECG includes ST elevation in leads V1–V3 with a right bundle branch block-like appearance. There may be evidence of a slowing of electrical conduction within the heart, as shown by a prolonged PR interval in some patients. These patterns may be present all the time but may appear only in response to particular drugs when the person has a fever, during exercise, or as a result of other triggers. The Brugada ECG pattern may become more obvious by placing the V1–V2 electrodes in high intercostal space positions.^[12]

The only effective treatment for the management of VF is an implantable cardioverter-defibrillator (ICD) implantation. However, in acute situations, the use of appropriate antiarrhythmic agents (example quinidine) in the treatment of intermittent or recalcitrant VF is advocated because of their potential to reduce mortality.

Case Report

This is a 44-year-old Taiwanese male who presented with a history of sudden loss of consciousness about 2 h after lunch. The patient also experienced recurrent sudden loss of consciousness while riding a motorcycle with his wife at about 4 p.m. There was no history of sudden turning of his head or change in body position prior to syncope. There was no history of convulsion, increased salivation, upward gazing, or urinary or fecal incontinence after syncope. There was no history of chest pain, chest tightness, jaw numbness, diaphoresis, visional defect, headache, head trauma, fever, and flu-like symptoms. He mentioned that he had intermittent palpitation, dizziness, and diaphoresis for about 4 years. He was diagnosed with hyperthyroidism on account of these symptoms 4 years ago but had reverted to euthyroid state without antithyroid agents. He was not on any medications and did not ingest any medication bought over the counter prior to the loss of consciousness. The patient reported that his father died suddenly some years back during the night without a known cause. There was no family history of diabetes mellitus, hypertension, dyslipidemia, or coronary artery disease. The patient regained conscious spontaneously and was taken to the emergency room (ER) of a local hospital for evaluation. At the ER, a brain computed tomography scan was performed, which was reportedly normal. The ECG revealed an ST-segment elevation with T inversion in V1–V2 leads with a normal cardiac enzyme. Under the impression of BrS, he was referred to the National Taiwan University Hospital for further evaluation. General physical examinations, cardiovascular system examination as well as other systems examinations were essentially normal.

Diagnosis

BrS is diagnosed by identifying typical persistent ECG pattern occurring concurrently with at least one of the following: documented evidence of ventricular arrhythmia (polymorphic VT or VF), arrhythmia-associated symptoms (syncope, seizure, or paroxysmal nocturnal dyspnea), and positive family history (SCD before the age 45 years, Type 1 ECG in relatives). The ECG pattern may become more evident by carrying out an ECG in which some of the electrodes are placed in different unusual positions.^[12] The ECG of patients with BrS shows three patterns^[11] [Figure 1].

Figure 1: Electrocardiogram of the Brugada syndrome (with permission to cite from Arthur Wilde et al. Circulation 106: 2514-2519, 2002.)

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Type 1 has a coved-type ST elevation with at least 2 mm (0.2 mV) J-point elevation and a gradually descending ST-segment followed by a negative T-wave
Type 2 has a saddleback pattern with a least 2 mm J-point elevation and at least 1 mm ST elevation with a positive or biphasic T-wave. Type 2 pattern can occasionally be seen in healthy controls
Type 3 has either a coved (Type 1 like) or a saddleback (Type 2 like) pattern, with <2 mm J-point elevation and <1 mm ST elevation. Type 3 pattern is not rare in healthy controls.

The 2013 expert consensus recommendations on inherited primary arrhythmia syndromes^[13] enumerated the following criteria for the diagnosis of BrS:

BrS is diagnosed if a patient has ST-segment elevation with Type 1 morphology ≥2 mm in at least one right precordial lead (V1 and V2) placed in the second, third, or fourth intercostal space, occurring either spontaneously or induced by intravenous administration of Class I antiarrhythmic agents (sodium channel blockers)
BrS is diagnosed if a patient has Type 2 or Type 3 ST-segment elevation with Type 1 in at least one right precordial lead (V1 and V2) placed in the second, third, or fourth intercostal space, occurring when a challenge test with intravenous administration of Class I antiarrhythmic agents evokes a Type 1 ECG morphology.

Our index case is a male Taiwanese of the Asian descent where BrS is found to be more common with a positive family history of SCD, as his father died suddenly without any known cause. Furthermore, he had a typical persistent ECG pattern consistent with BrS with an arrhythmia-associated symptom experienced as syncope. ECG performed with the leads placed at the usual positions showed Type 2 Brugada pattern [Figure 2]a. To increase the sensitivity of the ECG diagnosis of BrS, the ECG was performed by placing the right precordial leads (V1–V2) in the third intercostal space and subsequently in the second intercostal space (unusual positions). The leads V1–V2 showed typical Type 1 Brugada ECG [Figure 2]b and [Figure 2]c.

Figure 2: (a) Electrocardiogram of the Brugada syndrome showing type 1 (Coved) and type 2 (saddleback) patterns in leads V1 and V2, respectively, with a resting premature ventricular complexes when the V1 and V2 leads were placed on the fourth intercostal space. (b) Electrocardiogram of the Brugada syndrome showing type 1 (coved) patterns in leads V1 and V2 when the V1 and V2 Leads were placed on the third intercostal space. (c) Electrocardiogram of the Brugada syndrome showing typical type 1 (coved) patterns in leads V1 and V2 when the V1 and V2 leads were placed on the second intercostal space

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Differential diagnosis

The differential diagnosis includes medical conditions with ECG changes that mimic that of BrS. These will include hypercalcemia, hyperkalemia, acute myocardial ischemia, pericarditis, myocarditis, pulmonary embolism, acute stroke, aortic dissection, Duchenne muscular dystrophy, hypothermia, arrhythmogenic right ventricular dysplasia, pectus excavatum, electrical cardioversion, cocaine toxicity, and mechanical compression of the right ventricular outflow tract (RVOT).^[11],[14] These conditions must be excluded before the definitive diagnosis of BrS can be made^[15] as in our own case.

We checked serum potassium and calcium levels in our patient as he presented with ST-segment elevation in the right precordial leads. This is because both hypercalcemia and hyperkalemia may generate an ECG pattern similar to that of BrS. The results were essentially normal with serum calcium level of 2.35 mmol/L (2.15–2.58 mmol/L) and serum potassium level of 3.8 mmol/L (3.5–5.5 mmol/L).

An exercise stress test was performed in our patient to exclude ischemic heart disease and evaluate the ST-segment elevation in the peak phase. The patient exercised according to the BRUCE protocol for 07:31 min, achieving a workload of 10.1 metabolic equivalents (METs). The resting heart rate of 84 bpm rose to a maximal heart rate of 162 bpm. This value represents 92% of the maximal, age-predicted heart rate. The resting blood pressure of 125/81 mmHg rose to a maximum blood pressure of 182/75 mmHg. The exercise test was stopped due to dyspnea. The stress test was without evidences indicating ischemia. To completely exclude coronary artery disease and congenital coronary abnormality, coronary angiography was done for our patient and the result shows patent coronaries.

A chest X-ray was done as part of routine work after an ICD implantation and the report was essentially normal. Magnetic resonance imaging (MRI) of the heart with and without gadolinium enhancement was performed, using a 1.5T scanner (Aera, Siemens) with pulse sequences of T1w dark blood, cine steady state-free precession, T1 map, and late gadolinium enhancement mainly to exclude arrhythmogenic right ventricular cardiomyopathy and also to assess other potential causes of arrhythmias, such as hypertrophic or restrictive cardiomyopathy, unsuspected myocardial injury, myocarditis, or aberrant coronary origins. The result showed no significant abnormalities. Electrophysiologic study (EPS) was done to determine the inducibility of arrhythmias, in an effort to risk stratify our patient.

Risk stratification

High risk for a repeated arrhythmic attack is observed in patients with a history of surviving cardiac death or syncope of unknown origin and spontaneous type 1 ECG morphology.^{[15],[16],[17],[18],[19],[20]} This places our patient at high risk having had syncope of unknown origin with the ECG performed demonstrating spontaneous Type 1 ECG pattern. Evaluation of the clinical presentation of BrS probands over a certain period has been studied and documented.^[21] In one of those studies, newly diagnosed probands were significantly less symptomatic than those in the latter diagnosed group, with a lower prevalence of SCD as the first clinical presentation, spontaneous Type I ECG pattern, and less often inducible during electrophysiological study (EPS). Increased rate of arrhythmic episodes has been consistently associated with the male sex,^[22] and our index case is male. More so, increased incidence of syncope and VF in BrS patients has been associated with spontaneous atrial fibrillation (AF).^[23],[24] However, our patient did not have AF or inducible VF during EPS but had several episodes of documented VF by an ICD during follow-up. The syncope may be related to self-terminate VF. Large BrS registries could not confirm the value of right ventricular programmed electrical stimulation for estimating prognosis in BrS patients without a history of VT or VF,^[13],[19] whereas the presence of QRS fragmentation in leads V1–V3 and a ventricular effective refractory period <200 ms has been linked with a high rate of arrhythmic events in such patients.^{[13],[19],[23]} Our patient had a ventricular effective refractory period of <200 ms in the right ventricular apex and the RVOT, and this predisposes him to the risk of having a high rate of arrhythmic events. The place of EPS prognosticating BrS patients remains debatable.^[13]

Current treatment

Placement of implantable cardioverter-defibrillator

At present, implantation of an automatic ICD is the only treatment shown to be effective in the treatment of VT and fibrillation and preventing SCD^[16] in patients with BrS. No drug therapy has been found to reduce the occurrence of ventricular arrhythmias or sudden death.

Indications for ICD implantation were published in the report of the second consensus conference on BrS.^[25] For patients at the two extremes of risk stratification, the decision to implant or not to implant an ICD is relatively straightforward.

Patients with BrS and a history of cardiac arrest must be treated with an ICD. In contrast, asymptomatic patients with no family history of SCD can be managed conservatively with close follow-up, and ICD implantation is not recommended. Patients with intermediate clinical characteristics present the greatest challenge. Patients with syncope or cardiac arrest and suspected or diagnosed BrS must be hospitalized. Continuous cardiac monitoring is necessary until definitive treatment (i.e., ICD placement) can be provided. Our patient had a history of syncope and a family history of SCD and he received a single-lead MRI compatible St. Jude ICD implantation [Figure 3] as a definitive management of his condition to prevent SCD. After an ICD implantation, he had two episodes of recurrent near-syncope, one episode of syncope, and one episode of severe chest tightness and received four times of successfully appropriate ICD shocks for VF 1 week and 1 year later after an ICD implantation [Figure 3].

Figure 3: A single-lead magnetic resonance imaging compatible St. Jude implantable cardioverter defibrillator was implanted via the left subclavian vein

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Pharmacological treatment

Isoproterenol and quinidine were recommended in May 2013 by the international expert consensus for the treatment of BrS. They inhibit the short-term outward potassium current (Ito) or increase the sodium and calcium current. Isoproterenol enhances the L-type calcium current and has been found useful in the treatment of BrS patients with an electrical storm.^[26] However, there are no available controlled data on its therapeutic impact. Quinidine is an antiarrhythmic Class Ia drug with Ito and IKr inhibitor effects. It blocks the development of VF and prevents ventricular arrhythmias. Quinidine has been found useful in patients with repeated ICD shocks, a contraindication for ICD implantation, or supraventricular arrhythmias.^[27] More so, quinidine use in the treatment of children with BrS as a bridge or alternative to ICD implantation has been recommended in some studies,^[28],[29] though those studies were not randomized.

Radiofrequency catheter ablation

In their study, Nademanee et al.^[30] showed that epicardial ablation of the RVOT may block the initiation of VF in high-risk BrS patients. Although epicardial ablation is a more complicated procedure than endocardial ablation,^[31] in several studies of BrS patients with an implanted ICD due to VF, radiofrequency ablation prevented the short-term initiation of VF.^{[32],[33],[34]} In a study,^[35] in which 14 BrS patients had epicardial ablation of the RVOT and anterior right free wall, the ablation of the arrhythmogenic substrate halted the BrS phenotype. However, no randomized studies have shown the effectiveness of radiofrequency ablation as an ICD or as a first-line therapy for symptomatic or asymptomatic patients with BrS.

Conclusion

The first clinical presentation of BrS could be SCD due to VF. Most BrS patients are asymptomatic, and about two-third have a negative familial screening test. Large BrS registries could not validate the role of right ventricular programmed electrical stimulation for estimating the prognosis in asymptomatic BrS patients. The role of EPS for estimating prognosis in BrS patients is controversial, and ICD implantation is the only approved procedure to effectively prevent SCD in such patients. Some studies have reported the successful prevention of recurrent VF in high-risk patients with electrical storm after an ICD implantation through epicardial ablation of the RVOT.

Future randomized studies focused on risk stratification and the value of radiofrequency ablation in BrS patients are needed. Increasing awareness of BrS can improve a patient's diagnosis and management.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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