Approach

Brugada syndrome is usually diagnosed through a combination of clinical features, risk factors, and ECG findings, although the diagnosis is considered probable or definite if spontaneous type 1 Brugada pattern is recorded on ECG from the 2nd to 4th intercostal spaces.[1][4][7][51]​​​ Refer all patients with type 1 Brugada pattern (spontaneous or induced) to a cardiologist or cardiac electrophysiologist for further investigation. Key differentials, such as acute coronary syndrome, should be excluded. The proposed Shanghai score may also be used to aid diagnosis.​[1]

[Figure caption and citation for the preceding image starts]: Proposed Shanghai Score for diagnosis of Brugada syndromeAdapted from Peltenburg PJ et al. Neth Heart J. 31. 10.1007/s12471-022-01723-6​; used with permission [Citation ends].com.bmj.content.model.Caption@7271cffd[Figure caption and citation for the preceding image starts]: Diagnosis summary for Brugada syndrome [IMAGE KEY: EP = Electrophysiology; ICD = Implantable cardioverter defibrillator; ICS = Intercostal space; MRI = Magnetic resonance imaging; SCB = Sodium-channel blocker]Krahn AD, et al. Brugada syndrome. JACC Clin Electrophysiol 2022 Mar;8(3):386-405; used with permission [Citation ends].com.bmj.content.model.Caption@7514c904

History

Take a detailed history of any patient with suspected BrS to identify clinical features of BrS, risk factors for BrS and sudden cardiac death, and other potential differentials. This is particularly important for the diagnosis of BrS in patients with type 1 Brugada pattern on ECG that is induced by triggers (e.g., fever, medications such as sodium-channel blockers or psychotropic drugs, alcohol, or illicit drugs), and in asymptomatic patients with type 2 or 3 Brugada pattern on ECG.[1][7]

Clinical features

Consider a diagnosis of symptomatic BrS if a patient has a past history of any one or more of the following:

  • Unexplained cardiac arrest, or documented polymorphic ventricular tachycardia (PMVT), or ventricular fibrillation (VF)[1][5][7]

    • There are many causes of sudden cardiac arrest, PMVT and VF, but BrS should be considered as a differential, particularly if there is Brugada pattern on ECG and one or more risk factors for BrS (see below).

    • Patients may also present with monomorphic VT, but this is rare and should prompt investigation of other arrhythmogenic cardiomyopathies.[5][52][53]​​

  • Cardiogenic syncope

    • Up to one third of patients with BrS present with, or have a history of, syncope at the time of diagnosis.[54]

    • Take a careful history to differentiate cardiogenic from non-cardiogenic causes of syncope.[1][7]​​ The Shanghai score for the diagnosis of BrS assigns 2 points to patients with suspected cardiogenic syncope, and 1 point to those with an unclear cause of syncope.[1][49]​​

    • Patients with BrS who have a history of cardiogenic syncope are also at 2.5 to 5-fold greater risk of serious arrhythmic events compared with those with non-cardiogenic syncope.[47][48][55][56][57]​ Patients with non-cardiogenic syncope have not been shown to have an increased risk for serious arrhythmic events.[58]

Other clinical features of BrS may include:

  • Atrial fibrillation or flutter in a patient <30 years.[1][59][60]​​

    • Concomitant atrial arrhythmias are common in patients with BrS, with a prevalence of approximately 10%, although these are not specific for diagnosis of BrS.[61]

    • Use of sodium-channel blockers may unmask the Brugada pattern in some of these patients.[61]

  • Nocturnal agonal respirations.[1][7]

    • The Shanghai score for BrS assigns 2 points to patients with nocturnal agonal respirations.[1][49]

    • In a Danish national survey, prevalence of nocturnal agonal respirations in patients with BrS was 14%, but this is likely to be greater in endemic areas.[62]

    • Nocturnal agonal respirations were described in early reports from Southeast Asia (Philippines, Thailand, Japan, China, and others) of sudden unexpected nocturnal death syndrome (SUNDS), a syndrome which is thought to be genetically, phenotypically, and functionally the same as BrS.[63]

Risk factors

Identify any of the following risk factors which are associated with, or increase the risk of, BrS and subsequent sudden cardiac death:[1]

  • Age 30 to 50 years[1]

    • BrS is typically first diagnosed in young to middle-aged patients.[1]

    • Patients aged 30 to 50 years with BrS are also at high risk of serious arrhythmic events.[39]​ This is also typically the age at which patients with BrS may present with their first serious arrhythmic event.[1]​ However, serious arrhythmic events have also been reported in children as young as <1 year old.​[21][40][41]​​ Women in particular may be more likely to have their first SAE in childhood, or later in life.[1][39]

    • Patients >50 years who have BrS experience significantly fewer serious arrhythmic events compared with younger patients, and for those ≥55 years at the time of BrS diagnosis, annual mortality is similar to that of the general population.[41][42][43]​​​ However, it remains unclear whether these observations are due to protective effects acquired through ageing or simply represent selection bias. 

  • ​Male sex[1]

    • BrS is more common in men compared with women.[1][39]​ Men account for up to 90% of cases of BrS in some cohorts.[1][39]

    • Evidence has shown that men with BrS are also at increased risk of serious arrhythmic events.[44][45][46]​​​ However, this finding remains controversial, and has not been confirmed with complete adjustment for potential confounding factors.[47][48]​​

  • Asian ancestry[1]

    • ​BrS occurs more commonly in Asia compared with Europe and the US.​[1][13]​​ BrS is particularly common in Southeast Asia, where a nocturnal sudden death syndrome in young men was clinically reported by a variety of local names in countries such as Philippines, Thailand, Japan, and China, prior to the formal classification of BrS.[14]

  • Positive family history

    • Determine the following features (which form part of the Shanghai score) in any first or second degree relative of the patient:​[1][49]

      • Definite BrS

      • Suspicious sudden cardiac death (febrile, nocturnal, confounded by BrS-associated drug)

      • Unexplained sudden cardiac death <45 years with non-contributory autopsy.

    • Bear in mind that, although family history is a standard and important part of any diagnostic evaluation, limited evidence exists to support a family history of sudden death as a risk factor for BrS-associated arrhythmic events.[50]

Asymptomatic patients

Features of BrS may only be apparent when induced by certain factors.[1][7]​ Inducible features are particularly important to identify in asymptomatic patients (i.e., those who do not have a past history of unexplained cardiac arrest, ventricular arrhythmias, or syncope), but may also be present in symptomatic patients. These include:[1][7]

  • Febrile illness

    • Known to induce type 1 Brugada pattern on ECG and precipitate arrhythmic events.[1]​ In endemic regions, the prevalence of BrS in patients presenting with febrile illness for any reason has been reportedly as high as 4%, around 20 times greater than a non-febrile control group in one Thai cross-sectional study of 401 patients.[20][21]​ While in isolation fever is not specific for BrS, in a patient with suspected BrS, it has implications for both diagnosis and management.[1]

  • Medications

    • These include sodium-channel blockers (e.g., flecainide, procainamide), psychotropic medications (e.g., tricyclic or tetracyclic antidepressants, lithium), and local anaesthetics.

    • Known to induce type 1 Brugada ECG changes, and may also precipitate arrhythmic events.[1][18]

  • Illicit drugs or alcohol

    • Known to induce type 1 Brugada ECG changes and may also precipitate arrhythmic events.[1][18]

Physical exam

Perform a full cardiovascular examination to identify other causes of the patient’s clinical presentation. These include:

  • Acute coronary syndrome

  • Arrhythmogenic cardiomyopathy

  • Athlete’s heart

  • Haemodynamically significant valvular disease

  • Pectus excavatum

  • Incomplete right bundle branch block.

Although the physical exam is valuable in the overall evaluation of any patient, it is not useful to rule out or rule in a diagnosis of BrS.

Check whether the patient has a fever, which may unmask features of BrS.[1]

Initial investigations

ECG

Perform an ECG as the first line investigation for any patient with suspected BrS.[1]​​[5][7][18][64]​​ Look for the following patterns that may indicate BrS:[1][7]

  • Type 1: coved ST-segment elevation (J-point elevation with a gradual down-sloping ST-segment) ≥2 mm with a negative T-wave in the right precordial leads.[1][4][5][7][51]

    • Type 1 Brugada pattern may be spontaneous, or induced (e.g., by factors such as fever or sodium-channel blockers).[1][5][7]

  • Type 2 or 3: saddleback ST-segment configuration with variable levels of ST-segment elevation.[1][4][51]

Consider high precordial lead testing if ECG using standard lead placement is not conclusive and you have a high clinical suspicion of BrS. High precordial lead testing increases diagnostic yield by accounting for anatomical variations in right ventricular outflow tract anatomy.[1][4][5][65][66][67]

[Figure caption and citation for the preceding image starts]: Electrocardiographic patterns in Brugada syndrome showing type 1 (diagnostic) and types 2 and 3 (non-diagnostic) patterns. Type-1 (diagnostic): coved STT morphology in lead V2 with J-point elevation (dark grey line) of ≥0.2 mV (≥2 mm) and a terminal ST-segment elevation (light grey line, J+60 ms) also ≥0.2 mV (≥2 mm). Note the PR interval and wider QRS complex, wide and deep S in lead I, and fractionation in the right precordial ECG leads. Type-2 (non-diagnostic): saddleback STT morphology in lead V2 with J-point elevation (dark grey line) of ≥0.2 mV (≥2 mm) and a terminal ST-segment elevation (light grey line, J+60 ms) ≥0.1 mV (≥1 mm), followed by a positive T wave. Note the less wide and deep S-wave in lead I, less prominent fractionation. Type-3 (non-diagnostic): saddleback STT morphology in lead V2 with J-point elevation (dark grey line) of ≥0.2 mV (≥2 mm) and a terminal ST-segment elevation (light grey line, J+60 ms) <0.1 mV (<1 mm)Marsman EMJ et al. Heart 2022 May;108(9):668-75; used with permission [Citation ends].com.bmj.content.model.Caption@14a28d3c​​​​

[Figure caption and citation for the preceding image starts]: Standard- and high-lead ECG positions. (Top) Standard-lead ECG positions and corresponding precordial ECG in a patient with Brugada syndrome. (Bottom) High-lead ECG positions and corresponding ECG in the same patient. Note that hV5 and hV6 on the high-lead ECG correspond with V1 and V2 on the standard-lead ECG.Krahn AD, et al. Brugada syndrome. JACC Clin Electrophysiol 2022 Mar;8(3):386-405; used with permission [Citation ends].com.bmj.content.model.Caption@337b523a

Refer all patients with type 1 Brugada pattern (spontaneous or induced) to a cardiologist or cardiac electrophysiologist.

  • The diagnosis of BrS is considered probable or definite if spontaneous type 1 Brugada pattern is recorded on ECG from the 2nd to 4th intercostal spaces.[1][4][7][51]​​​ However, these patients require diagnostic evaluation by a specialist.

  • Ensure you establish the patient’s clinical history in all patients with type 1 Brugada pattern.[4]

  • This is essential, because distinguishing type 1 Brugada pattern from other causes of ST elevation using ECG alone can be difficult, even for an experienced cardiologist.[4]

  • If the patient has induced type 1 Brugada pattern, additional information is key to aid diagnosis of BrS (e.g., relevant clinical history or family history, and/or genetic testing).[1]

If the patient has type 2 or 3 Brugada pattern, consider provocative drug testing with sodium channel blockade (see below).[1][18]

Echocardiogram

Organise an echocardiogram for any patient being evaluated for BrS to assess for underlying structural heart disease and to rule out other causes of their presentation.​[1][49]​​ Echocardiogram is often normal in BrS or may demonstrate mild structural abnormalities in the right ventricle or right ventricular outflow tract.

Other investigations

Provocative drug testing with sodium channel blockade

Consider provocative drug testing with sodium-channel blockers (e.g., procainamide, flecainide) for any patient with both:[1][7][13][18][49]​​​​

  • Type 2 or 3 Brugada pattern on ECG

    AND

  • Suspected BrS due to relevant clinical signs, symptoms, or family history.

The diagnosis of BrS is considered probable in these patients if type 1 Brugada ECG pattern is provoked during drug testing with sodium-channel blockers; this scores two points on the Shanghai score.[1]​ Refer these patients to a cardiologist or cardiac electrophysiologist.

Due to an associated risk of inducing life-threatening ventricular arrhythmias, provocative drug testing should only be performed by experts under optimal circumstances.[68]

Sodium-channel blocker test is not recommended in patients with a prior type I Brugada pattern.[7]

Genetic testing

Arrange genetic testing in patients with type 1 Brugada pattern on ECG (spontaneous or induced); this helps facilitate family screening of first degree relatives.[1][18][69]​​​​​ However, the presence of a susceptible gene mutation is not diagnostic of BrS. This is in part due to only 50% penetrance of genetic variants. Clinical presentation remains central to diagnosing Brugada syndrome.[1]

Probable pathogenic mutation in a BrS susceptibility gene also scores 0.5 points on the Shanghai score.[1] Mutations of many genes have been implicated in BrS, but only SCN5A gene variants are considered definitely disease-causing.[1][7]​​ However, identifiable SCN5A variants are only found in approximately 20% to 30% of patients with BrS.[1][7][16][17][18]​​​[64]​​ Mutations of other genes only account for around 2% to 5% of cases.[14][16][17]​​[19]

Advanced cardiac imaging (MRI or CT)

Consider other advanced imaging modalities, such as cardiac MRI or CT, if the diagnosis of BrS is uncertain to help differentiate BrS from other differentials, such as arrhythmogenic cardiomyopathy.[36][70]​ See Differentials.

Invasive electrophysiological (EP) study with inducibility testing for ventricular arrhythmias

Invasive EP studies with inducibility testing (including measurement of baseline intervals, programmed electrical stimulation [PES], and electroanatomical mapping) may be considered following consultation with an electrophysiologist or cardiologist with expertise in managing BrS if the patient has asymptomatic BrS and is deemed intermediate risk on risk stratification. See Management approach for more information about risk stratification.[7][64]​​ Although there is debate regarding the prognostic value of PES in primary electrical diseases, there is some evidence to consider its use in BrS.​[64][71]

Invasive EP assessments have demonstrated voltage abnormalities recorded from the right ventricular epicardium of patients with BrS in the absence of cardiac MR or CT structural abnormalities.[38]​ This highlights the importance of expert consultation if you suspect BrS, but the diagnosis is unclear.

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