Mr. A is a 42-year-old male with a medical history of hypertension who presented to the ED with moderate-to-severe lightheadedness over the past few days, not associated with any activities. The dizziness is a new symptom that is not provoked by position changes, exercise, prolonged standing, or the Valsalva maneuver. Mr. A described his dizziness as feeling weak and faint, lasting only a few seconds for each episode. He had no sensation of the room spinning, feeling warm, diaphoresis, or nausea.
However, the episodes have been increasing and now average two to three per day. The patient denies loss of consciousness, generalized weakness, changes in vision or hearing, chest pain, shortness of breath, or palpitations, and has no history of seizure disorder, anxiety, depression, or trauma. In addition, there has been no recent travel, sick contacts, fevers or chills, ataxia, appetite or dietary changes, weight loss, or weight gain.
Mr. A's only medication is hydrochlorothiazide 25 mg daily for BP control, and he has no allergies. The patient is married, works as an office assistant, and does not exercise. Mr. A drinks one cup of coffee per day and does not drink alcohol or use illicit drugs or tobacco products. Significant family medical history includes hypertension and type 2 diabetes mellitus in his father and heart disease and death from sudden cardiac arrest at the age of 44 in his mother.
Mr. A's vital signs were as follows: oral temperature 98.2° F (36.8° C), pulse 94, respiratory rate 18, BP 132/86, height 5' 7”, weight 171 lbs (77.6 kg), and oxygen saturation of 98% on room air. The patient's orthostatic BP and heart rate were obtained in the sitting, standing, and supine positions at 122/78 (88), 126/79 (89), and 120/77 (86), respectively.
The physical exam revealed a well-developed, well-nourished young man in no acute distress. Mr. A's cardiovascular exam included regular heart rate and rhythm, normal S1 and S2, absence of murmurs, rubs, and gallops, and no jugular venous distension. Lung sounds were clear to auscultation bilaterally, without wheezes, crackles, or rhonchi, and there was no accessory muscle use. His abdomen was soft and nontender, without hepatomegaly or splenomegaly, and bowel sounds were present in all four quadrants. The neurological exam revealed no nystagmus, unsteady gait, or focal deficits. Femoral, dorsalis pedis, and posterior tibial pulses were 2+ bilaterally, and there was no clubbing of the nails or peripheral cyanosis or edema.
An ECG was performed that revealed a normal sinus rhythm at 72 beats per minute, QRS complex of 0.12 seconds, right bundle-branch block and ST-segment elevation in leads V1 and V2 with negative T waves in leads V1 and V2 (see Patient's ECG). Initial lab testing included a complete blood count, basic metabolic panel, and cardiac enzymes (creatine kinase and troponin), which were all within normal limits (see Lab values at admission). Imaging studies included a chest X-ray, carotid ultrasound, and an echocardiogram, which were also normal (see Imaging studies).
Based on Mr. A's presentation, physical exam, and lab and imaging studies, the patient's most likely diagnosis was determined to be Brugada syndrome (BrS). He underwent cardiac catheterization, which revealed normal coronary arteries and a left ventricular ejection fraction of 50%. The patient also underwent electrophysiology studies, which provoked sustained ventricular tachycardia, requiring cardioversion to achieve sinus rhythm. Given this finding, a single-lead implantable cardioverter defibrillator was implanted for the primary prevention of sudden cardiac death. Mr. A remained stable and was discharged home the following day.
BrS is an uncommon but potentially fatal cardiac disorder, as it may elicit ventricular tachyarrhythmias.1 This syndrome should be considered when sudden cardiac death occurs in previously healthy individuals. The etiology of BrS is a genetic mutation, with an autosomal dominant pattern of the inherited component, which leads to abnormality of the cardiac sodium channels.1 The expression of the genetic mutation is variable, and many factors may contribute to the electrocardiographic and clinical manifestations of the syndrome. The incomplete penetrance and the variable expression of the causal genetic mutations means that the disorder can be absent in parents and other relatives of affected individuals, so a negative family history does not necessarily rule out the disorder.2,3
The first pathogenic mutation was found to be in the SCN5A gene, which was discovered in 1998.1,3 This mutation results in defects of cardiac sodium ion transport channels, leading to potentially fatal ventricular cardiac arrhythmias.4 Since this discovery, many other genes with pathogenic mutations have been identified to be associated with the cardiac sodium, potassium, and calcium channels.1,2 However, among all cases of BrS, only about 35% were found to be associated with a genetic mutation. About 30% of patients had the SCN5A gene mutation and about 5% had other genetic mutations.1-3
ECG changes include ST-segment elevations in leads V1 and V2 and right bundle branch block. BrS may be responsible for 4% to 12% of all cases of sudden cardiac death but may also present clinically as near-syncope, syncope, ventricular tachycardia, or simply characteristic ECG abnormalities discovered in an asymptomatic patient.1,4 Global prevalence is estimated at 5 to 20 in 10,000 but is difficult to determine because detection is complicated by both transient normalization of ECG findings and missed diagnoses.1 Geographically, the highest prevalence is in Southeast Asia, with Thailand specifically exhibiting prevalence 14 times the world average.8 BrS is more common in men than in women (8:1), and is usually first diagnosed around age 40, although age may range widely from 1 to 84.1,2,4 Women with BrS are less likely to be symptomatic, as these patients typically display a more benign clinical presentation and are less likely to have a type 1 ECG pattern.3,6 Although presentation in the pediatric population is rare, children presenting with symptomatic BrS are at high risk of ventricular arrhythmias.
Diagnosis. The diagnosis of BrS is normally made after a clinical event, such as syncope or cardiac arrest. These patients are usually considered healthy and without any contributing factors for the presenting symptoms, such as structural heart defects.3 Because the physical exam is normal in most patients, making the diagnosis can be difficult.9 There are two main types of ECG patterns associated with BrS: type 1 and type 2. A type 1 BrS ECG pattern involves a coved-type (J-wave) ST-segment elevation 2 mm or greater in leads V1 and/or V2 with a negative T wave.3,4,10-12 A type 2 BrS ECG pattern is distinguished by a saddleback or downsloping of the ST-segment elevation to the isoelectric line, which could result in either a positive T wave or biphasic T wave (see Type 1 and type 2 ECG patterns).4,9,13
A definitive diagnosis of BrS can be established based on symptoms and the presence of the type 1 BrS ECG pattern, as discussed by the second Brugada Consensus Report.3,12 This pattern must be elicited spontaneously during an electrophysiology study or induced by a sodium channel blocker challenge.3,4 In patients with type 1 BrS ECG pattern who are otherwise healthy and asymptomatic, the presence of any of the following clinical findings may be valuable in strengthening the diagnosis: absence of structural heart disease; presence of a first-degree atrioventricular block and left axis deviation; atrial fibrillation; ST-T wave alternans with spontaneous ventricular premature beats in a left bundle-branch block pattern; and fragmented QRS (narrow QRS with the presence of R' wave or notching of R or S wave).3,14
BrS should be strongly considered in patients with a type 2 BrS ECG pattern, which includes an ST-segment elevation in at least one right precordial lead (V1 and V2) at baseline that can be converted to the type 1 pattern during a sodium channel blocker challenge.3,4,12 At least one of the following must be present: documented ventricular fibrillation; polymorphic ventricular tachycardia; family history of sudden cardiac death before the age of 45 years; inducible ventricular tachycardia during electrophysiology studies; unexplained syncope; family history of type 1 BrS ECG pattern; or nocturnal agonal respirations.2,3,9,12
Further testing should be performed to rule out other underlying causes of the patient's symptoms and ECG pattern, which includes but is not limited to echocardiogram or cardiac MRI to assess for structural heart defects; cardiac enzymes to rule out myocardial infarction; and electrolytes, such as sodium, potassium, and calcium to rule out potential causes for the ECG changes.3,9 Furthermore, genetic testing for the SCN5A gene would be helpful in diagnosis.9 For risk stratification, electrophysiology studies are extremely important to assess for underlying, potentially dangerous arrhythmias.9
Differential diagnosis. In addition to BrS, differential diagnoses for Mr. A include cardiovascular, neurologic, or vestibular system disorders. Peripheral vestibular dysfunction, psychiatric disorders, medication adverse reactions and, less likely in our younger patient, cerebrovascular disease, remain important considerations in the absence of clinical symptoms or findings consistent with cardiac disease.3,4,12
Hypercalcemia, hyperkalemia, early repolarization, atypical right bundle branch, pulmonary embolism, and acute myocardial infarction may result in ECG findings that mimic BrS, which were all ruled out from the patient's workup.9 This patient's clinical presentation combined with a family history of sudden cardiac death, characteristic findings on the ECG, and the occurrence of ventricular tachycardia during electrophysiology studies led to the diagnosis.
Treatment and management. The treatment for BrS is limited. An implanted cardiac defibrillator has been proven to be the best option, since it is the most effective method in managing cardiac arrhythmias and preventing sudden death.9,11 Attempts to utilize pharmacotherapy have been made with antiarrhythmic drugs, such as quinidine, bepridil, cilostazol, isoproterenol, isoprenaline, and orciprenaline (metaproterenol).4 However, to date, prior studies have not proven medications to be effective and were found to be associated with a high incidence of adverse reactions, including tachyarrhythmias.1,4,9,11 As a result, pharmacotherapy should not be considered the standard of care.1,4 To minimize the risk of tachyarrhythmias, patients diagnosed with BrS should avoid certain medications, including class 1a and 1c antiarrhythmics, psychotropic medications, and some anti-anginal and anesthetic drugs. Other common substances such as cocaine, alcohol, and cannabis should also be avoided.4,9 For patients with frequent electrical storms, epicardial ablation may be a promising option.11 It was found that in BrS patients, the underlying electrophysiologic mechanism is due to a delayed depolarization over the anterior aspect of the right ventricular outflow tract epicardium. Ablation of this abnormality helps to prevent episodes of ventricular tachycardia as well as normalization of the BrS ECG pattern.15
Of note, children presenting with symptomatic BrS are at high risk of ventricular arrhythmias and may be candidates for implantable cardioverter defibrillator placement.7
Patient education and perspective. Mr. A was educated on his condition and the severity of the disease. He verbalized understanding of the disease process, provided informed consent, and agreed with the treatment options. He and his first-degree relatives were referred for genetic counseling and testing.
BrS is a rare but potentially lethal inherited autosomal dominant disorder that requires immediate identification and management. An implanted cardiac defibrillator is the only treatment with a proven benefit. Genetic screening can confirm the diagnosis and identify silent carriers.1 Future advances in identifying genetic determinants hold the potential to identify patients at risk who would benefit from interventions before expression of symptoms. At the present time, patients with BrS should be treated according to risk profiles, with genetic testing reserved for diagnostic purposes and strongly considered for assessing risk in family members.
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