Color Atlas and Synopsis of Electrophysiology, 1st Ed.

55. ECG CRITERIA AND DRUG CHALLENGE AS DIAGNOSIS FOR BRUGADA SYNDROME

Ruben Casado Arroyo, MD, PhD, Kristel Wauters, MD, Pedro Brugada, MD, PhD.

CASE PRESENTATION

A 7-year-old child with a family history of sudden cardiac death (SCD) was admitted in our center because of several episodes of syncope. Due to the clinical history, an ajmaline test was performed. The test was stopped early (0.4 mg/kg) due to a positive result (Figures 55-1A and 55-1B). During the following minutes, the ECG shows severe abnormalities of the ventricular repolarization and some episodes of nonsustained ventricular tachycardia (Figure 55-1C). The patient was asymptomatic. An infusion of isoprenaline was started reversing the abnormalities in the ECG.

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FIGURE 55-1 (A) Basal ECG of a 7-year-old child (type 2). (B) ECG positive for Brugada syndrome (type 1) during ajmaline infusion. The infusion was stopped after the positive result. (C) NSVT observed two minutes after stopping the infusion of ajmaline.

CONCEPT

Brugada syndrome is an autosomal-dominant, inherited channelopathy characterized by ST-segment elevation or J wave in the right precordial leads. First described in 1992,1 the syndrome is associated with a high incidence of SCD secondary to a rapid polymorphic VT or VF in patients with structurally normal hearts.

EPIDEMIOLOGY

The prevalence of the Brugada ECG pattern is variable, ranging from 3% in endemic areas of Southeast Asia to 0.61% in Europe. In the United States, the prevalence ranges from 0.012% to 0.43%. However, because the diagnostic ECG pattern can be intermittently present or concealed, it is difficult to estimate the true prevalence of the disease in the general population.2-4 In up to 60% of patients the disease can be sporadic. Although the disease is inherited as an autosomal-dominant, there is a male predominance in its phenotype. It suggests-that gender- and age-related factors (eg, sex hormones) may play a role in triggering the arrhythmia in Brugada syndrome. The age of onset of clinical manifestations (syncope or cardiac arrest) is the third to fourth decade of life.5

ETIOLOGY AND PATHOPHYSIOLOGY

The ST-T wave changes in Brugada syndrome likely reflect a profound change in the process of ventricular repolarization. Three different theories have attempted to explain the syndrome: the depolarization theory, the repolarization theory, and the neural crest theory.6-8

DIAGNOSIS

The diagnosis of Brugada syndrome (BS) requires the presence of a type 1 BS pattern in the right precordial leads (ie, V1-V3), either spontaneous or unmasked by class I antiarrhythmic drugs (Table 55-1), characterized by a prominent coved ST-segment elevation displaying J-point amplitude or ST-segment elevation ≥2 mm, followed by a negative T wave. The type 2 BS pattern (≥2 mm J-point elevation, ≥1 mm ST-segment elevation, and a saddleback appearance, followed by a positive or biphasic T wave), and type 3 BS pattern (either a saddleback or coved appearance, but with an ST segment elevation <1 mm) are considered to be suggestive but not confirmatory of the disease (Figure 55-2).

TABLE 55-1 Drugs Used to Unmask Brugada Syndrome

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FIGURE 55-2 ECG patterns associated with Brugada syndrome. (A) Type 2 ECG (suspicious); (B) Type 1 ECG (diagnostic).

The diagnosis of BS is based on clinical diagnostic criteria (Table 55-2). Right bundle branch block may be associated with BS, but its presence is not required for the diagnosis (Figure 55-3). The drug challenge test involves administration of ajmaline, flecainide, procainamide, or pilsicainide under close cardiac monitoring and in a setting that is equipped for resuscitation. Procainamide remains the only choice for intravenous pharmacological induction protocols in the United States, despite consensus that both ajmaline and flecainide appear to be more efficacious. The drug challenge test is finished when (1) the diagnostic type 1 ST-segment elevation develops, (2) the ST segment elevation in type 2 ECG pattern increases by at least 2 mm, (3) PVCs or other arrhythmias develop, or (4) the QRS widens by 30% or more. Although the drug challenge test is generally safe, it can potentially precipitate malignant cardiac arrhythmias or advanced AV block, particularly in patients with preexisting intraventricular conduction disturbances (wide QRS complex) or infranodal AV conduction delay. Isoproterenol and sodium lactate can be effective antidotes in this setting.

TABLE 55-2 Diagnostic Criteria of Brugada Syndrome.

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FIGURE 55-3 Diagnostic algorithm for Brugada syndrome.

Diagnostic genetic testing may be considered for patients who clinically manifest with symptoms of Brugada syndrome. Although the knowledge of a specific mutation may not provide guidance for determining prognosis or treatment, identification of a disease-causing mutation in the family can lead to genetic identification of at-risk family members who are clinically asymptomatic and who may have normal ECGs. However, it is important to remember that a negative result of genetic testing does not exclude the presence of the disease and, therefore, only a positive genetic diagnosis is informative.

DIFFERENTIAL DIAGNOSIS

A group of diseases may cause development of ST-segment elevation in the right precordial leads, mimicking the BS ECG pattern (Table 55-3). Exposure to some drugs and ionic imbalance may produce a Brugada-like pattern, which may represent a genetic predisposition to BS (Table 55-4). Fever also modulates the phenotype and risk of arrhythmias in BS patients by causing accentuation of the inactivation of the Na+ channel, showing a type 1 ECG pattern and triggering ventricular arrhythmias.

TABLE 55-3 Differential Diagnosis of ECG Abnormalities That Can Lead to ST-Segment Elevation in V1-V3

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TABLE 55-4 Drugs That Can Lead to ST-Segment Elevation in V1-V3.

 

Cocaine intoxication

Alcohol intoxication

Treatment with:

Antiarrhythmic drugs:

• Na channel blockers (class Ic, class Ia)

• Calcium channel blockers

• β-Blockers

Antianginal drugs:

• Calcium channel blockers

• Nitrates

Psychotropic drugs:

• Tricyclic antidepressants

• Tetracyclic antidepressants

• Phenothiazines

• Selective serotonin reuptake inhibitors

• Lithium

MANAGEMENT

Currently, an ICD is the only proven effective treatment for Brugada syndrome. ICD implantation is recommended in patients with type 1 Brugada ECG (either spontaneously or after Na+ channel blockade) and a history of aborted SCD or related symptoms such as syncope, seizure, or nocturnal agonal respiration, given that noncardiac causes of these symptoms have been carefully excluded. ICD devices need to be carefully programmed in Brugada syndrome patients in order to avoid inappropriate shocks, given the high incidence of supraventricular arrhythmias in this population. Programming a single VF zone of more than 210 beats/min with a monitor is preferable.

PATIENT EDUCATION

Fever may induce the appearance of a type 1 BS ECG pattern and may trigger episodes of ventricular arrhythmias in BS patients. In the case of fever, close ECG monitoring is appropriate in combination with lowering body temperature. BS patients should be advised to avoid all drugs that may induce a type 1 ECG or trigger ventricular arrhythmias.9 All BS patients must be followed-up on a regular basis, in order to identify the development of symptoms.

REFERENCES

1. Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol. 1992;20(6):1391-1396.

2. Rossenbacker T, Priori SG. The Brugada syndrome. Curr Opin Cardiol. 2007;22(3):163-170.

3. Campuzano O, Brugada R, Iglesias A. Genetics of Brugada syndrome. Curr Opin Cardiol. 2010;25(3):210-215.

4. Morita H, Zipes DP, Wu J. Brugada syndrome: insights of ST elevation, arrhythmogenicity, and risk stratification from experimental observations. Heart Rhythm. 2009;6(Suppl 11):S34-S43.

5. Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association.Circulation. 2005;111(5):659-670.

6. Coronel R, Casini S, Koopmann TT, et al. Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada syndrome: a combined electrophysiological, genetic, histopathologic, and computational study. Circulation. 2005;112(18):2769-2777.

7. Antzelevitch C. The Brugada syndrome: ionic basis and arrhythmia mechanisms. J Cardiovasc Electrophysiol. 2001;12(7):268-272.

8. Elizari MV, Levi R, Acunzo RS, et al. Abnormal expression of cardiac neural crest cells in heart development: a different hypothesis for the etiopathogenesis of Brugada syndrome. Heart Rhythm. 2007;4(3):359-365.

9www.brugadadrugs.org