Sudden Arrhythmic Death Syndrome

Sudden arrhythmic death syndrome (SADS) is sudden unexpected death in a person over 1 year of age, usually under 40 years, when a full autopsy with histology and toxicology finds no structural, toxic or other cause. A fatal arrhythmia is presumed.

A survivor of cardiac arrest with a documented shockable rhythm and no cause has idiopathic ventricular fibrillation, not SADS.

SADS accounts for about a quarter to a half of sudden deaths under 35 years, with an incidence of about 1 to 2 in every 100,000 each year. Men account for about two thirds, and many deaths occur at rest or in sleep.

Family evaluation gives a diagnosis in about 20 to 40% of families, most often long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, or a cardiomyopathy missed at autopsy.

Molecular autopsy finds a likely pathogenic variant in about 15 to 25% of decedents, mainly in KCNQ1, KCNH2, SCN5A and RYR2.

Related entities are sudden unexplained death in epilepsy, sudden infant death (under 1 year), sudden unexplained death in childhood (1 to 18 years) and sudden unexplained nocturnal death syndrome in South-East Asia.

Pathophysiology. Most cases are inherited channelopathies with low penetrance, or cardiomyopathies with changes too subtle to show at autopsy. A trigger (exertion, fever, drug, noise, sleep, electrolyte shift) provokes ventricular fibrillation in a susceptible heart.

The presenting problem is a bereaved family, with relatives who are usually well. Information to collect:

• Circumstances of death: exertion, swimming, sleep, loud noise, emotion, fever, drugs or alcohol.
• Prior symptoms in the decedent: syncope, seizure like episodes, palpitations, exercise intolerance.
• Three generation pedigree: sudden death under 50 years, drowning, single vehicle accidents, epilepsy, sudden infant death, pacemakers and defibrillators, and known cardiomyopathy or channelopathy.
• Relatives: syncope, palpitations, a past ECG, and drug and sport history. Examination and resting ECG are usually normal.

Post-mortem.

• Full autopsy by a cardiac pathologist: heart weight and measurements, coronary arteries, valves, myocardial sampling of all ventricular walls and septum, and conduction system histology.
• Toxicology of blood, vitreous and urine, including cardioactive drugs. Vitreous biochemistry. Microbiology if infection is suspected.
• Frozen tissue (spleen or heart) and EDTA blood stored for DNA.
• Molecular autopsy on a panel of channelopathy and cardiomyopathy genes. Variants of uncertain significance are not used alone for cascade testing.

First degree relatives (second degree if none available), in a specialist clinic:

• History, examination, 12-lead ECG (including leads V1 and V2 placed in the second and third intercostal spaces), echocardiography, exercise test, ambulatory ECG for 24 to 48 hours, and cardiac MRI when other tests are abnormal or the family history is strong.
• Sodium channel blocker challenge in adults when Brugada syndrome is suspected: flecainide 2 mg/kg intravenously over 10 minutes (maximum 150 mg), or ajmaline 1 mg/kg intravenously over 5 minutes, with a defibrillator at hand. Positive when coved ST elevation of 2 mm or more appears in V1 or V2. Stop for QRS widening of over 130% of baseline or ventricular arrhythmia.
• Epinephrine challenge (0.05 to 0.2 microgram/kg/min intravenously, with defibrillation available) when long QT syndrome is suspected and the QT fails to shorten.
• Genetic testing targeted to the decedent's variant, otherwise a panel in the relative with a phenotype.
• Children are reassessed every 1 to 2 years until adulthood, because phenotypes evolve.

Differential diagnosis.

• Subtle arrhythmogenic or hypertrophic cardiomyopathy
• Myocarditis
• Anomalous coronary artery and coronary spasm
• Conduction system disease and pre-excitation
• Drug or stimulant effect, alcohol and electrolyte disturbance
• Epilepsy related death and unrecognised pulmonary embolism
• Sudden infant death and sudden unexplained death in childhood

The aim is to find a cause and prevent a second death in the family.

Treatment of relatives by diagnosis.

• Long QT syndrome: nadolol 0.5 to 1 mg/kg/day orally in one or two doses, increased to 1 to 1.5 mg/kg/day, maximum 2 mg/kg/day, long term. Extend the interval to every 24 to 36 hours at creatinine clearance 31 to 50 mL/min, every 24 to 48 hours at 10 to 30 mL/min, and every 40 to 60 hours under 10 mL/min. Contraindicated in asthma, severe bradycardia and high grade atrioventricular block without a pacemaker. Avoid QT-prolonging drugs, keep potassium at 4.5 to 5.0 mmol/L, and treat vomiting and diarrhoea early.
• Catecholaminergic polymorphic ventricular tachycardia: nadolol 1 to 1.5 mg/kg/day orally in one or two doses (maximum 2 mg/kg/day) with flecainide 50 mg orally twice daily, increased to 100 to 150 mg twice daily (children 2 to 3 mg/kg/day), maximum 300 mg daily. Reduce when the QRS widens by over 25%. Start at 50 mg twice daily at creatinine clearance of 35 mL/min or less. Contraindicated in structural heart disease.
• Brugada syndrome: avoid sodium channel blockers, tricyclic antidepressants and excess alcohol. Treat fever early with paracetamol 1 g orally every 6 hours (maximum 4 g daily, 3 g in liver impairment or weight under 50 kg). Implantable defibrillator after arrest or arrhythmic syncope. Quinidine sulphate 200 to 300 mg orally every 8 hours (maximum 1,200 mg daily in this setting) for recurrent arrhythmia, with ECG, full blood count and liver enzyme monitoring.
• Cardiomyopathy: treatment by the specific disease.
• Idiopathic ventricular fibrillation in a survivor: implantable defibrillator, ablation of triggering ventricular premature beats, and quinidine sulphate 200 to 300 mg orally every 8 hours (maximum 1,200 mg daily in this setting) for recurrent storm, with ECG, full blood count and liver enzyme monitoring.

Relatives with no diagnosis. No drug. Give a written list of drugs to avoid, treat fever promptly, teach family members CPR, and keep a defibrillator accessible. Competitive sport is decided after full assessment. Repeat evaluation every 2 to 3 years in adults, and sooner with symptoms or a change in the family.

Genetics and support. Pre-test and post-test counselling, with consent and privacy safeguards. Review variants of uncertain significance every 1 to 2 years and repeat testing after 2 to 5 years. Bereavement support for the family.

Special groups. Pregnancy in a woman with a confirmed channelopathy: continue the beta blocker and plan delivery with defibrillation available. Region: where autopsy and genetic testing are unavailable, evaluate first degree relatives clinically, store DNA when possible, and record the circumstances of death.

Monitoring. Device interrogation every 3 to 6 months, ECG after each dose change, and yearly review in affected relatives. Flecainide level and QRS width after dose changes.

Referral and escalation. Refer the family to an inherited cardiac conditions service. Urgent for any relative with syncope, ventricular arrhythmia or a diagnostic ECG.