Variable presentation of Brugada syndrome: lessons from three generations with syncope

Introduction

General practitioners see many patients with syncope but in only a few cases is this due to a primary cardiac arrhythmia. Nevertheless, identifying such patients is important because some familial arrhythmias are associated with a risk of sudden death. We describe how a recently defined arrhythmia, Brugada syndrome, caused syncope in three generations of one family. The cases show the importance of taking an adequate family history when assessing patients with syncope and how this information is crucial to diagnosis and management.

Brugada syndrome is an inherited cardiac disease causing ventricular tachyarrhythmias in patients with structurally normal hearts.1 Since its first description in 1992, the number of cases reported worldwide has grown substantially, and it is thought to account for many cases of unexpected sudden death.

The syndrome is characterised by a history of syncope or cardiac arrest and a characteristic electrocardiographic pattern: right bundle branch block and ST segment elevation in V1 to V3. Most cases are inherited as an autosomal dominant trait, explaining a strong family history of syncope or sudden death.2 Some patients have normal resting electrocardiographic appearances but the classic changes can be induced by giving ajmaline, an antiarrhythmic drug.3

Case 1

A 27 year old woman presented with three episodes of sudden loss of consciousness over six weeks. She had no palpitations and no consistent precipitants. On each occasion she was unconscious for a few seconds before regaining consciousness. She had had similar episodes when she was 7 years old. These had been investigated by a neurologist, but no diagnosis had been made. In the intervening years she had been symptom free.

Examination showed no abnormality, but her resting electrocardiogram showed partial right bundle branch block (fig 1). Twenty four hour cardiac monitoring and echocardiography gave normal results. However, a patient activated electrocardiograph showed ventricular tachycardia during a symptomatic spell. An electrophysiological study showed ventricular tachycardia during ventricular stimulation. She had magnetic resonance imaging of the heart to rule out right ventricular dysplasia, and this showed no abnormality.

Fig 1

Resting electrocardiogram of case 1 showing partial right bundle branch block with normal precordial ST segments

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In view of the electrocardiogram and the recurrent ventricular tachycardia, in a structurally normal heart, a diagnosis of Brugada syndrome was made. A cardioverter defibrillator was implanted to prevent any life threatening arrhythmias. Since then she has remained well.

Case 2

The mother of case 1, a 49 year old woman, had had idiopathic epilepsy diagnosed for many years. Since the age of 7 years she had had episodes of dizziness and loss of consciousness. The episodes were variable in nature and occasionally associated with chest pain, sweating, and fitting activity, such as rigidity and shaking of the limbs.

After her daughter had Brugada syndrome diagnosed, she was referred to the cardiologist who had been looking after her daughter. Her resting electrocardiogram appeared normal, but an ajmaline test provoked changes consistent with Brugada syndrome (fig 2). She had a cardioverter defibrillator inserted and has since been free of symptoms.

Fig 2

Electrocardiograms from case 2, taken while resting (top) and after being given ajmaline (bottom). Note ST segment elevation in V1-V3 after ajmaline

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Case 3

The woman in case 1 had an 8 year old son with Down's syndrome. Trisomy 21 (47 XY,+21) with partial atrioventricular septal defect was diagnosed after birth. He had corrective surgery for the atrioventricular septal defect at 3 years of age. Before this surgery he had collapsed several times in what were thought to be drop attacks. The attacks resolved after the cardiac surgery.

He presented to hospital aged 6 years after an episode of collapse associated with cyanosis and unconsciousness. His electrocardiogram showed partial right bundle branch block, which was attributed to his previous cardiac surgery. Results of 24 hour cardiac monitoring and electroencephalography were normal.

He continued to have dizzy spells and collapses, culminating in a severe episode at school, three months after his mother had Brugada syndrome diagnosed. The episode was witnessed by his teacher, who reported that his pulse rate was extremely rapid during the attack. Subsequent investigations confirmed that he had Brugada syndrome, and he has remained free of symptoms since the insertion of a cardioverter defibrillator.

Discussion

The family history of patients with syncope should be carefully evaluated for evidence of familial causes of sudden cardiac death. The commonest of these is hypertrophic cardiomyopathy, which has an estimated prevalence of 1:500 to 1:5000.4 Other causes include hereditary arrhythmias (such as long QT syndromes and Brugada syndrome) and hereditary structural defects (such as arrhythmogenic right ventricular dysplasia). These conditions are rare compared with other causes of syncope. Careful history taking and simple investigations are therefore needed to identify patients who warrant referral for specialist assessment.

Diagnosing Brugada syndrome is not straight-forward as it exists in many forms. The syndrome is inherited as an autosomal dominant trait, but expression varies—for example, the typical electrocardiographic pattern is often absent or transitory.5 The syndrome is most common in men of South East Asian origin, but it has been described in many different age groups and ethnic origins.5

Our report shows the difficulty in diagnosing Brugada syndrome in atypical cases. Case 2 had symptoms but normal resting electrocardiographic appearances. Diagnosis in such patients depends on unmasking concealed conduction abnormalities by giving intravenous antiarrhythmic drugs such as ajmaline. This test is useful because symptomatic patients are at risk of sudden death if left untreated.6

Case 2 also illustrates the difficulty in distinguishing cardiac causes of loss of consciousness from neurological causes. Investigations in all cases of unexplained syncope should include resting and 24 hour electrocardiography. However, normal results do not exclude Brugada syndrome, and if the patient is at risk an ajmaline test should be considered.

Diagnosis is further complicated by unrelated conditions such as right ventricular dysplasia, in which the electrocardiogram may show the typical Brugada-like pattern and the patient is prone to sudden arrhythmic death.7 Structural heart disease must therefore be excluded before diagnosing Brugada syndrome.

Identification of a genetic abnormality is helpful in distinguishing Brugada syndrome. Furthermore, identification of a recognised mutation will facilitate screening of relatives. The genetic defect is a mutated cardiac sodium channel gene (SCN5A) on chromosome 3.8 The mutant sodium channel shortens the cardiac action potential, making parts of the cardiac tissue vulnerable to re-entry circuits. There are several recognised mutations causing Brugada syndrome, but in many cases a recognised mutation is not found. Such genetic heterogeneity may explain the heterogeneity of expression between individuals.

The prognosis for patients with Brugada syndrome is poor unless they are treated. Mortality is thought to be up to 10% a year.5 Drug treatment is not effective, but an implantable cardioverter defibrillator has been shown to prevent sudden death.3